Showing posts with label early salvage. Show all posts
Showing posts with label early salvage. Show all posts

Tuesday, September 20, 2016

Very early salvage radiation has up to 4-fold better outcomes and saves lives

Another  subject that has come up a lot recently is when to have salvage radiation. It is always a pressing decision for those 30% of prostatectomy patients who have detectable PSA after prostatectomy. We have seen (see this link) that a low PSA on an ultrasensitive PSA test, as low as 0.03, can be a predictor of full biochemical recurrence later. This latest analysis of this subject looked at how treating sooner rather than later was associated with better cancer control and survival.

Abugharib et al. examined the records of 657 men who had salvage radiation therapy (SRT) from 1986 to 2013 at the University of Michigan and the University of Texas Southwestern. They were all discovered to have detectable PSA following prostatectomy. Researchers were looking for evidence to confirm or contradict their hypothesis that earlier SRT had better outcomes.

They defined "earlier" in two ways:

1. At a lower PSA. Because of the treatment dates, there was relatively little data from ultrasensitive PSA tests. They divided PSA at the time of SRT into three categories:
  • 0.01-0.2 ng/ml - the "very early salvage" cohort
  • >0.2 - 0.5 ng/ml - the "early salvage" cohort
  • >0.5 ng/ml - the "later salvage" cohort (0.5 was selected because the median PSA was 0.4 ng/ml)
2. At an earlier time from completion of prostatectomy
  • < 9 months   
  • 9-21 months
  • 22-47 months
  • > 48 months
They looked at "outcomes" in four ways:
  1. freedom from biochemical recurrence (PSA> 0.2 ng/ml) after SRT
  2. freedom from starting salvage, life-long androgen deprivation therapy (ADT) after SRT
  3. freedom from detectable metastases after SRT
  4. prostate cancer specific survival
After a median follow-up of 9.8 years, they found:
  • The time in months since completion of prostatectomy had no bearing on any of the outcomes.
  • The PSA at which they were treated has a major impact on all outcomes.
  • The "early salvage" group had outcomes that were about twice as poor as those who had "very early salvage." This was true after correcting for all the variables (like Gleason score and positive margins) that would have made a difference.
  • The "later salvage group" had outcomes that were about four times as poor as those who had "very early salvage." This was true after correcting for all the variables (like Gleason score and positive margins) that would have made a difference.
  • 91% of the variance in biochemical recurrence after SRT was explained by the PSA at which patients were treated.
  • Adjuvant ADT, which was given to 24% of patients for a median of 6 months (range 4-24 months), was significantly associated with freedom from biochemical recurrence after SRT. There were 40% fewer failures. 
Researchers did not have data on PSA doubling time and velocity, and the number who had persistently elevated PSA, all of which almost certainly would affect outcomes. Perhaps such other variables as the length of the positive margins and the Gleason score there ought to be incorporated into a fuller analysis.

Patients who were treated at an early sign of detectable PSA  (0.2-0.5) were twice as likely to develop metastases and die of prostate cancer as those who were treated at the earliest PSA (below 0.2). Those who waited for PSA to rise above 0.5 ng/ml were four times as likely to develop metastases and die from prostate cancer compared to those treated when PSA first became detectable.

We have three large randomized clinical trials proving that outcomes are diminished by about half by waiting rather than treating within the first 6 months, even before there are detectable PSAs (called adjuvant radiation). But few elect to have adjuvant radiation, and the number has been declining (see this link). To avoid overtreatment and protect patients from perhaps unnecessary side effects of SRT, early salvage has emerged as a compromise.

The authors point out that it may take 7 months or more for adequate healing of urinary and erectile complications (see this link). Also, this is an important decision for the patient, which he ought not make hastily. Yet here, more than in the primary therapy decision, very early action can save lives. As a compromise, they suggest early use of neoadjuvant ADT (prior to SRT) which could slow the cancer down and give tissues more time to heal. The extra time may help the patient recover better urinary function, if not erectile function.

They recommend,
"Our data would suggest potentially a traditional cut-off of 0.2 to define biochemical failure may be too late, and that at the first sign of a detectable PSA that SRT (or SRT + ADT) should be initiated."
This remains a difficult decision, and the patient with a detectable PSA after surgery should begin discussions with a good radiation oncologist as soon as possible. Age and comorbidities enter into the decision as well. Unfortunately at these low PSAs, even the most accurate of the new generation of PET scans are incapable of finding distant metastases that might help rule out those cases where SRT would be futile. Nomograms and Decipher scores may help in cases where the decision is equivocal.

Tuesday, August 30, 2016

Extraprostatic extension (EPE) alone is not enough to justify adjuvant radiation

Patrick Walsh and Nathan Laurentschuk wrote an opinion piece in European Urology taking issue with the 2013 AUA/ASTRO recommendation that adjuvant radiation is indicated for men with a pathological finding of extraprostatic extension (EPE, stage pT3a) after surgery, regardless of the surgical margin status. The combination of EPE and negative surgical margins is the most common adverse finding, accounting for 60% of them. Therefore, the AUA/ASTRO guideline would lead to gross overtreatment if it were followed. They believe that it is fortunate that that guideline is increasingly ignored (see this commentary).

They looked at the three randomized clinical trials of adjuvant radiation vs. wait-and-see, for evidence that EPE alone justified adjuvant radiation.
  • ·      Although it concludes that all patients with EPE should have adjuvant radiation, SWOG 8794 never looked at that subgroup separately.
  • ·      In ARO 96-02, men with EPE and negative margins received no statistically significant benefit in terms of freedom from biochemical failure from adjuvant radiation.
  • ·      Not only was there no benefit, but EORTC 22911 found a 78% increased risk of dying among men with EPE and negative margins who received adjuvant radiation.

They conclude with a set of recommendations about adjuvant radiation:

Who should NOT receive it:

• Men with extraprostatic extension (capsular penetration) with negative margins

• Men aged >70 yr unless they are very healthy and have high grade or positive margins

• Men with bladder neck contractures or significant incontinence who have marginal indications

Who should receive it:

• Men with Gleason ≥7 with positive surgical margins

Marginal benefit:

• Men with positive seminal vesicles

In a commentary published in Practice Update, Christopher King, a radiation oncologist at UCLA, takes tissue with their recommendations. He argues that until the findings of randomized clinical trials provide more reliable data, current evidence does not justify adjuvant radiation based only on adverse pathology. Instead, based on several retrospective studies (reviewed on this site), he advocates waiting for some evidence of measurable disease. He believes that early salvage (before PSA rises above 0.2 ng/ml) will have equivalent oncological outcomes to adjuvant radiation, but will avoid the toxicity of overtreatment.

Metastases after early vs. delayed salvage radiation

Until we have the results of randomized clinical trials on the relative efficacy of early salvage radiation, we have to look for other clues to inform the timing of that decision. Adjuvant radiation carries a high risk of overtreatment, whereas delayed salvage may preclude the window of opportunity during which salvage radiation might have been curative.

Den et al. posted the outcomes of their investigative analysis at the ASCO Genitourinary Conference (Abstract 12). Data on 422 patients treated at 4 institutions were retrospectively analyzed. All had adverse pathology (either stage T3 or positive margins) after RP. Patients were arbitrarily divided according to their PSA after surgery at the time they received radiation:
  • ·      <0.2 ng/ml – “adjuvant RT” (111 patients)
  • ·      >0.2 but <0.5 ng/ml – “early salvage RT” (70 patients)
  • ·      >0.5 ng/ml – “delayed salvage RT” (83 patients)
  • ·      No radiation received (157 patients)
CAPRA-S scores and Decipher genomic classifier scores were found to independently predict risk of metastatic progression. Adjusting for those scores:
  • ·      Delayed salvage RT increased risk of metastases by 4.3 times over adjuvant RT
  • ·      No radiation increased risk of metastases by 5.4 times over adjuvant RT
  • ·      Early salvage and adjuvant RT had about the same risk of metastases
  • ·      Men with low CAPRA-S and Decipher scores had low risk of metastases
  • ·      Men with high CAPRA-S and Decipher scores benefit from adjuvant RT, but had high rates of metastases nonetheless.

This study once again underscores the importance of early salvage radiation for curative therapy after failed surgery when there is adverse pathology. They didn’t investigate the use of ultrasensitive PSA to determine what the lowest level that avoids overtreatment might be. Adverse pathology and PSA are important to consider, but other clinical/genomic factors can contribute to the decision-making process as well. Low Decipher scores can help rule out those cancers that are unlikely to metastasize in the next 5-10 years. However, it is less useful at indicating those cancers that will metastasize.  And there are no good tests for determining if the cancer is already systemic and micrometastatic, in which case salvage radiation would be futile. This remains a challenging situation for discussion between the patient and radiation oncologist.

Monday, August 29, 2016

Johns Hopkins: ultrasensitive PSA after surgery predicts biochemical relapse

We’ve looked at several retrospective studies this year that found that early ultrasensitive PSA (uPSA) results following surgery can reliably predict eventual biochemical relapse. Johns Hopkins examined its own database and found the same thing.

The study by Sokoll et al.  looked at the records of 754 men treated with surgery at Johns Hopkins between 1993 and 2008 whose first post-surgery PSA, taken at about 3 months, was “undetectable” (<0.1 ng/ml). They reanalyzed the stored serum samples using an ultrasensitive PSA assay that could detect values of 0.01 ng/ml or higher. Each man was tracked until biochemical recurrence (BCR) – defined as PSA≥0.2 ng/ml – or for at least 5 years if there was no biochemical recurrence (median of 11 years).
  • ·      Among men whose first uPSA was ≥ 0.01 ng/ml, about half eventually had BCR.

o   57% were BCR-free at 5 years, 49% at 11 years.
o   Mean BCR-free survival: 10 years
  • ·      Among men whose first uPSA was < 0.01 ng/ml, 87% remained BCR-free.

o   92% were BCR-free at 5 years, 86% at 11 years.
o   Mean BCR-free survival: 15 years
  • ·      Among men whose first uPSA was ≥ 0.03 ng/ml, 77% eventually had BCR.

o   27% were BCR-free at 5 years, 22% at 11 years.
o   Mean BCR-free survival: 5.5 years
  • ·      Among men whose first uPSA was < 0.03 ng/ml, 85% remained BCR-free.

o   91% were BCR-free at 5 years, 84% at 11 years.
o   Mean BCR-free survival: 15 years

Other predictors of recurrence were the usual suspects: initial PSA, pathological stage and Gleason scores, and the presence of positive margins.

They additionally tracked a cohort of 44 men who’d had a cystoprostatectomy for bladder cancer in order to determine whether extra-prostatic sources of PSA might interfere with the uPSA test’s sensitivity to detect recurrent prostate cancer. All but two had uPSA<0.01 ng/ml, and those two had low values, 0.01 and 0.02 ng/ml.

So we see that a uPSA cutoff of 0.01 ng/ml on a first test is no better than a coin toss at predicting eventual BCR, and would lead to a great deal of overtreatment. On the other hand, a uPSA cutoff of 0.03 ng/ml correctly predicted eventual BCR 77% of the time. It missed about 15% of the men who would eventually recur, but was no worse than the lower cutoff in this regard. Clearly, a uPSA cutoff of 0.03 ng/ml is prognostic of BCR and a lower cutoff is not. The authors seem to miss this point in their conclusion.

Their analysis seems congruent with the other studies we’ve seen lately. Koulikov et al. also found that the 0.03 ng/ml cutoff was prognostic, but only when uPSA was increasing steadily. Kang et al. also found that a cutoff of 0.03 ng/ml at any time after surgery optimized BCR predictions with a median 18-month lead-time advantage among men diagnosed with adverse pathology (pT3 and/or positive margins). In a separate analysis among men with more favorable pathology (pT2, irrespective of margin status), Kang et al. found that a cutoff of 0.03 ng/ml on a first uPSA was predictive of later (median of 33 months) BCR.

While we await more definitive results from randomized clinical trials, there seems to be an emerging consensus that 0.03 ng/ml is the optimal uPSA cutoff. Using a lower cutoff for early salvage or adjuvant RT will lead to overtreatment, and there seems to be no risk attached to waiting for it. Provisionally, I believe it should be viewed as a surrogate for the traditional BCR definition.

Sunday, August 28, 2016

Declining trend in the utilization of adjuvant radiation.

A recent report in European Urology found that in spite of three randomized clinical trials (RCTs) that proved the efficacy of immediate or adjuvant radiation following surgery with adverse pathology results compared to a wait-and-see approach, a lower%age of such patients are getting adjuvant treatment. Why should this be?

I refer readers to a recent discussion of the issues involved, which I won’t fully reiterate here. First, let’s look at the report by Sineshaw et al. The authors examined the records of 97,270 patients in the National Cancer Database where patients were found to have adverse pathological features (pT3/4 or positive surgical margins) in the period from 2005-2011. What they found is this:

·      Postoperative RT utilization declined from 9.1% to 7.3%.
·      Utilization declined with age: 8.5% in patients aged 18–59 to 6.8% in patients aged 70–79. 
·      Utilization was 14% at community cancer programs compared to 7% at teaching/research centers.
·      Among those with stage pT3/4, utilization was 17% if they had positive margins, but 7% if they had negative margins.
·      Utilization was 17% among those with pathology Gleason score of 8-10 compared to 4% among those with Gleason score  of 6 or less.

First, a note about the timeframe examined in their study: only one of the three RCTs  (Thompson et al. 2009) was published in that timeframe. The Bolla et al. study was not published until 2012, and the Wiegel et al. study was not presented until 2013. The AUA/ASTRO guidelines advocating adjuvant radiation were not issued until 2013. So in the timeframe examined in their study, we would not expect to see the full impact of those three studies and the new guidelines. This conflicts with the statement made in the publication:
In a retrospective analysis of 97 270 patients with prostate cancer, we showed that use of postoperative radiotherapy for adverse pathologic features has declined over time after the publication of findings from major randomized clinical trials and consensus guidelines supporting consideration of such therapy.”

A report in Medscape included comments from some illustrious radiation oncologists that are worth noting:
·      Jeffrey Michalski  (Washington University, St. Louis) echoed the authors’ anachronistic lament that doctors were not following the evidence in the RCTs and guidelines.
·      Anthony D’Amico (Dana-Farber and Brigham and Women’s Hospital) pointed out that only one of the RCTs showed an advantage in metastasis-free and overall survival. He further explained that multiple risk factors may be a better indication for adjuvant radiation.
·      Michael Zelefsky (MSKCC) noted that we don’t yet know if waiting for rising PSA would have any worse outcomes.
·      Howard Sandler (Cedars-Sinai) blamed low utilization on urologists who don’t immediately refer adverse pathology patients to radiation oncologists. They are not given options or provided with expertise.

Until the results of ongoing clinical trials on the benefit of early salvage radiation become available, this remains a difficult decision. A patient with adverse pathology should immediately begin discussions with a radiation oncologist, preferably at a teaching/research hospital, so that he fully understands what the risks and benefits are of waiting.

Saturday, August 27, 2016

Does early salvage radiation save lives?

Several studies have tried to address the issue of whether adjuvant radiation actually increases prostate cancer survival in the long term compared to waiting. They all showed that biochemical progression-free survival could be improved by earlier treatment, but it remained questionable whether that would eventually translate into a survival benefit.

After 10 years of follow-up, the randomized clinical trial ARO 96-02 found that neither metastasis-free survival nor overall survival was significantly improved by adjuvant radiation. However, the study was underpowered to reliably detect those results.

After 10 years of follow-up, the randomized clinical trial EORTC trial 22911 found that adjuvant radiation did not significantly improve overall or metastasis-free survival, although there may be benefit for men less than 70 years of age, or those with positive margins.

There was only one study, SWOG S8794, which after 12.6 years of follow-up, demonstrated a significant improvement in both overall and metastasis-free survival among patients who had adjuvant radiation compared to patients who waited. However, the difference did not hold up when patients who received adjuvant radiation were compared to those who received salvage radiation. The difference was possibly attributable to the fact that very few patients in the wait-and-see arm ever got salvage radiation.

None of those three studies used radiation doses that are now considered to be adequate for curative adjuvant or salvage radiation.

So, with highly equivocal findings from the best studies we have available so far, how is the patient to make a decision as to whether it is worthwhile to undergo the potential side effects of early salvage radiation? This is the question that Hsu et al. at the University of California San Francisco set out to answer by looking for evidence in their large CaPSURE database. They identified 305 patients who had radiation after surgery, and who had such high-risk features on their surgery pathology report as:
  • ·      Positive surgical margins, or
  • ·      Gleason score 8-10, or
  • ·      Stage T3 or T4

In that group, they found
  • ·      76 men who had undetectable PSA and received adjuvant radiation within 6 months of surgery.
  • ·      229 men who had salvage radiation after reaching a PSA>0.1 ng/ml, or after 6 months post-surgery. This group comprised:

o   180 who had early salvage radiation before PSA reached 1.0 ng/ml
o   49 who had late salvage radiation after PSA reached 1.0 ng/ml

After a median elapsed time of over 6 years after surgery, the researchers found:

  • ·      Overall, 98% were still alive.
  • ·      Overall, 12% had progressed to metastases or death.
  • ·      Adjuvant and salvage radiation patients had comparable high-risk features.
  • ·      Men who had salvage radiation had an all-cause mortality rate 2.7 times higher than men who had adjuvant radiation.
  • ·      Men who had salvage radiation had a prostate cancer-specific mortality rate 4.0 times higher than men who had adjuvant radiation.
  • ·      Ten year estimated prostate cancer-specific mortality was:

o   12% among men who had adjuvant radiation.
o   16% among men who had early salvage radiation.
o   29% among men who had late salvage radiation.
  • ·      Late salvage radiation carried increased risk of prostate cancer-specific mortality and all-cause mortality.
  • ·      Early salvage radiation had about the same mortality risk as adjuvant radiation.

The conclusion is that early salvage radiation, while PSA is still below 1.0 ng/ml, had the same survival benefit as adjuvant radiation, but without the risk of overtreatment. However, waiting until after PSA reached 1.0 ng/ml significantly increased the risk of metastases and prostate cancer mortality.

The PSA threshold used in this study, 1.0 ng/ml, is quite high and well beyond the limit used for the definition of biochemical recurrence (0.2 ng/ml). It may turn out to be the case that this higher threshold is a more useful definition of biochemical recurrence than the current definition. However, the follow-up period here is short (median 6 years), as it may require 20 or 30 years for a survival benefit to show up when a lower threshold is used. It should also be noted that the definition of “adjuvant” radiation used in this study included therapy begun anytime before PSA reached 0.1 ng/ml, while there may be greater survival advantage when adjuvant radiation is begun at a lower level measured on an ultrasensitive PSA test.

While this study provides evidence for early salvage radiation, its retrospective nature makes it subject to selection bias: there may have been specific reasons why the patients were selected to receive adjuvant, early salvage or late salvage radiation. The abstract of the study makes no mention of the radiation doses used, whether androgen deprivation was used along with the radiation, the use of radiation to pelvic lymph nodes, or whether age and co-morbidities were significantly different. We await the results of ongoing randomized clinical trials to provide more reliable information.

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..