How soon after surgery should salvage radiation begin?

Patients and their doctors often have to make a critical decision soon after surgery – at what point after surgery, if at all, should salvage radiation therapy be started? Immediate treatment is often too early, and waiting can be too late. Two new papers give us much-needed help in finding the “Goldilocks moment.”

 Let’s begin with a shared understanding of the definitions of some commonly used terms and abbreviations:

• Adverse pathology means that the post-op pathology report indicates that cancer was found in one or more of the following places:
  • Outside of the prostate capsule (pathological stage T3a), or
  • In the seminal vesicles (pathological stage T3b), or
  • Locally, but at a distance from the prostate (pathological stage T4), or
  • At the surgical margin, where the surgeon has cut through the cancer — a “positive surgical margin” (PSM).
• Adjuvant radiation therapy (aRT) means radiation given after prostatectomy when there is adverse pathology, but before the PSA becomes detectable.
• Salvage radiation therapy (sRT) means radiation given after prostatectomy but also only after a biochemical recurrence (BCR).
• Early salvage radiation therapy (early sRT) means radiation given after the point that aRT would be given, but before sRT would be given.
• Wait-and-see is the strategy of waiting until after a BCR to decide what to do. The wait-and-see decision may be sRT at any time after BCR, or the patient may decide to forgo radiation, use hormone therapy, or do nothing until there is evidence of clinical progression.
• Biochemical recurrence (BCR) post-surgery is now defined as a confirmed PSA ≥ 0.2 ng/ml. This was chosen in 2007 because it was the most frequently used threshold in published studies. When those studies began, a PSA of 0.1 ng/ml was as low as could reliably be measured. Anything below that was undetectable at the time, and 0.2 ng/ml was arbitrarily deemed a biochemical recurrence.
• An ultrasensitive PSA (uPSA) test is any PSA test that can reliably detect PSAs below 0.1 ng/ml. While the definition of biochemical recurrence has not been changed, detectable levels of PSA are now as low as 0.001 ng/ml on some commercially available ultrasensitive tests.

The above definitions can be illustrated as potential decision points along a line showing uPSA values after prostatectomy and adverse pathology:

Why start sooner than sRT/wait-and-see, but later than aRT?

Three major randomized clinical trials have shown that there is an oncological advantage to aRT over a wait-and-see strategy in patients with adverse pathology after prostatectomy. This is hardly surprising, especially because “wait-and-see” includes patients who never even received salvage radiation, or may have only received palliative hormone therapy. There has never yet been a randomized clinical trial comparing aRT to sRT.

Based on those studies, both the American Urological Association (AUA) and the American Society of Radiation Oncologists (ASTRO) endorse aRT in their guidelines. However, in spite of those guidelines, only 43 percent of men who get radiation after prostatectomy do so within the first 6 months of their surgery (see Sheets et al.). Why aren’t more patients choosing aRT?

Patients (and many doctors too) worry about over-treatment, and the adverse effects of radiation on recently cut tissues. Immediate aRT may represent over-treatment for many men for whom small, detectable amounts of PSA are leaked into the serum from benign tissue left behind by surgery, or men in whom any tiny amounts of malignant tissue left behind may be indolent or susceptible to scavenging by the immune system. Kang et al.found that, among men with capsular perforation, PSMs, or seminal vesicle invasion after surgery, only 17 percent actually went on to have a true biochemical recurrence. The other advantage to waiting is that it may allow for better recovery of continence and erectile function after surgery in at least some patients.

All three of those above-mentioned clinical trials accrued participants before uPSA tests became routinely available. Although the use of uPSA testing is controversial, its widespread use has led many patients and clinicians to wonder whether waiting for some low PSA value – “early salvage radiation” – might be equivalent in outcomes to aRT.

There are randomized clinical trials underway in Canada and the UK, in Australia and New Zealand, and in France to determine whether early sRT might be equivalent to aRT in terms of survival. The combined results of those trials may have sufficient power to answer the question. Those findings will be definitive, but in the meantime two groups of researchers have retrospectively analyzed their patient outcomes for clues.

Ultrasensitive PSA reliably predicts eventual biochemical recurrence (a UCLA study)

Researchers at the University of California, Los Angeles (UCLA) looked at available evidence that the uPSA test might afford radiation oncologists the opportunity to treat patients late enough that they are assured to be on a path to clinical recurrence, yet early enough that waiting for treatment does no oncological harm. Kang et al. conducted a retrospective analysis of data from 247 patients treated at UCLA between 1991 and 2013 who were found on post-op pathology to have adverse disease characteristics — stage pT3-4 disease and/or positive surgical margins — and who received uPSA tests. That cohort had the following characteristics:

• Positive margins in 79 percent of patients
• Patients were excluded if
  • They had already received radiation and/or hormone therapy, or
  • They were found to be node-positive at the time of surgery
• Pathological stage T3/T4 in 55 percent of patients
• Gleason score ≥ 7 in 81 percent of patients
• Initial, pre-surgical PSA ≥ 10 in 29 percent of patients
• Time to first post-op PSA, 3 months
• Median number of PSAs post-surgery and before subsequent treatment, 4
• Median follow-up, 44 months

Kang et al. found that a uPSA ≥ 0.03 ng/ml was the optimal threshold value for predicting biochemical recurrence (BCR). Other findings included:

• uPSA ≥ 0.03 ng/ml was the most important and reliable predictor of BCR. It predicted all relapses (no false negatives: no one was under-treated), and hardly ever predicted relapses incorrectly. Only 2 percent would be over-treated by waiting for this cut-off.
• It was especially prognostic if found on the first uPSA test after surgery.
• Even if the first uPSA test was undetectable, any subsequent test where uPSA ≥ 0.03 ng/ml predicted BCR.
• Other lesser predictors of recurrence were pathologic Gleason grade, pathologic T stage, initial PSA before surgery, and surgical margin status.
• At 5 years of follow-up, 46 percent of patients had a BCR using the “standard” PSA ≥ 0.2 definition, 76 percent using the PSA ≥ 0.03 definition.
• Treating when an ultrasensitive PSA level reached 0.03 ng/ml gave a median lead time advantage of 18 months over waiting until PSA reached 0.2 ng/ml.
• It was necessary to monitor PSA for at least 5 years post-op, and to test at least every 6 months.

What is not known at this time is whether there is a survival disadvantage from waiting until uPSA reaches 0.03 ng/ml if it is not at that level immediately after surgery. (update 10/2018)  Kang et al. report that there is indeed a survival advantage from treating if the first uPSA level (at 3 months after surgery) reaches 0.03 ng/ml. So the lead-time advantage actually translates to a survival advantage for men with adverse pathology who have a persistent uPSA of at least 0.03 ng/ml.

If the findings of this study by Kang et al. are confirmed by randomized clinical trials, there is certainly a strong argument that all patients with adverse post-op characteristics should be monitored routinely using ultrasensitive PSA tests, and offered treatment with salvage radiation when their PSA level reaches 0.03 ng/ml. It is also arguable that the definition of biochemical recurrence after prostatectomy should then be changed to 0.03 ng/ml, which would be more practical.

Ultrasensitive PSA can reliably predict eventual biochemical recurrence at 2 months after surgery (a Czech study)

A Czech study (Vesely et al. and updated here) looked at a group of 116 patients (205 updated) who had PSMs after surgery. Unlike the UCLA study, staging was not a selection criterion. The two studies’ goals were somewhat different. While the UCLA study didn’t start uPSA testing until 3 months after prostatectomy, in this study uPSA testing was begun at 2 weeks post-surgery. Most urologists wait for 3 months because surgery sheds a lot of PSA into the serum, and it takes a while for that excess to clear out. The goal in this study was to find out just how early in time after prostatectomy they could detect a uPSA prognostic for BCR, whereas the UCLA study sought to find out how late in uPSA progression they could detect a PSA prognostic for progression. The Czech cohort had the following characteristics:

• Only patients with PSMs were included
• Patients who received aRT or hormone therapy were excluded
• Pathological stage T3/T4 in 54 percent of patients
• Gleason score ≥ 7 in 51 percent of patients
• Initial, pre-surgical PSA ≥ 9.2 in 50 percent of patients
• Time to first post-op PSA, 14 days

All patients’ PSA levels were measured on days 14, 30, 60, 90, and 180 post-surgery, and at 3-month intervals thereafter; the median follow-up was 31 months.

Vesely et al. found that the uPSA on day 30 had predictive accuracy of 74 percent for recurrence, and reached a maximum of 84 percent by day 60, when the uPSA was 0.04 ng/ml (increases in accuracy afterwards were not statistically significant). The following table summarizes their findings:

• Applying the uPSA cut-off at day 60 as the indicator for sRT would result in the decrease of over-treatment from 53 to 4 percent. Of the 33 percent who would be under-treated, 86 percent would eventually be discovered at subsequent follow-up at 3 months, and 98 percent by 4 years.
• uPSA at day 14 was not prognostic for recurrence.
• The following were not predictors of recurrence in men with PSMs: pathologic Gleason grade, pathologic T stage, initial PSA before surgery.
• Neither the location nor the extent of PSMs had any significant impact on the frequency of BCR.
• At 5 years of follow-up, 47 percent of patients had a BCR using the “standard” PSA ≥ 0.2 definition.

The main conclusion of this study is that uPSA tracking can begin earlier. Even as early as 30 days post-op, uPSA has good accuracy for predicting BCR in men with PSMs, and at 60 days, the accuracy is even better. If duplicated in larger studies, this implies that uPSA testing ought to begin 1 or 2 months earlier than it usually does at present.

The predictive accuracy of this study is somewhat lower than the UCLA study, perhaps in part because the sample size was half as big. The results in terms of uPSA prognostic threshold values, however, are surprisingly similar. Here, the threshold was 0.04, 0.01, and 0.02 ng/ml at 2, 3, and 6 months, respectively. In the UCLA study, the threshold was 0.03 ng/ml at any time from 3 months onward. Because the uPSA ≥ 0.03 at 90 days and onwards was 100 percent predictive of BCR in the UCLA study, and led to almost no under-treatment, it may well obviate the need for earlier uPSA testing advocated in the Vesely et al. study.

As in the UCLA study, however, it is not yet known whether early sRT translates to a survival advantage over waiting for BCR.

For the first time, these studies give the patient and doctor new insight into the timing and use of uPSA to predict BCR. If confirmed, setting a uPSA threshold at about 0.03 ng/ml would reduce over-treatment compared to aRT, and would reduce under-treatment compared to sRT. We await the completion of three randomized clinical trials before we have more reliable data.

written 1/4/2015

How early salvage radiation therapy can be used to prevent metastases and save lives

While several clinical trials have established that adjuvant radiation reduces the risk of biochemical recurrence, but only one looked at and demonstrated an improvement in metastasis-free survival and prostate cancer-specific survival. That one (see this link), only compared adjuvant radiation to “wait-and-see,” and a third of the men with a biochemical recurrence were never given salvage radiation. Some retrospective studies (see this link and this link) suggested that salvage radiation could improve metastasis-free and prostate cancer-specific survival, particularly if begun within 2 years of biochemical recurrence and when PSA doubling time (PSADT) is long.

Stish et al. examined the records of 1,106 patients who received salvage radiation therapy (SRT) at the Mayo Clinics between 1987 and 2013. They wanted to determine whether, with a large enough sample size and long enough follow-up, they could show patient characteristics and treatment variables that are associated with salvage radiation saving lives and increasing metastasis-free survival. With a median of 9 years of follow-up, they found that:

• ·      64 percent had a second biochemical recurrence within 10 years after SRT

o   Biochemical recurrence was higher among men with higher stage, positive lymph nodes, higher Gleason scores, and shorter PSADTs prior to SRT.

o   Biochemical recurrence was lower among men with longer time to reach detectable PSA, those who had adjuvant androgen deprivation therapy (ADT) for more than a year, those who had an SRT dose ≥ 68 Gy, and those who received SRT since 2008.

• ·      20 percent had distant metastases within 10 years after SRT

o   Incidence of distant metastases was higher among men with higher stage, positive lymph nodes, higher Gleason scores, and shorter PSADT prior to SRT.

• ·      10 percent died of prostate cancer within 10 years after SRT

o   Prostate cancer mortality was higher among men with higher stage, higher Gleason scores, and shorter PSADT prior to SRT.

• ·      23 percent died of all causes within 10 years after SRT

o   All-cause mortality was higher among men who were older, and those with higher stage, higher Gleason scores, and shorter PSADT prior to SRT.

As we’ve seen in so many radiation studies, adequate radiation dose (of about 70 Gy) and long-term ADT (see this link) are important for success of SRT. Outcomes are better when patients are treated when the disease has had less time to progress.

Now that use of SRT is declining, it is particularly important to show which patient and treatment variables may aid SRT in saving lives. Although current AUA/ASTRO guidelines advocate adjuvant and salvage RT, we have seen (see this link) that utilization is declining among men with adverse pathology after prostatectomy.

The authors performed a secondary analysis to determine whether it is safe to wait for a higher PSA prior to SRT. It is not. They arbitrarily used a cut-off of 0.5 ng/ml. Post-SRT biochemical recurrence, distant metastases, and prostate cancer mortality were all worse among those who did not receive SRT until PSA was over 0.5 ng/ml.

It’s important not to misinterpret this to mean that a patient can wait for his PSA to rise to 0.5 ng/ml before opting for SRT. This cut-off was chosen quite arbitrarily. Many patients were not diagnosed with a recurrence at lower PSA levels (this analysis includes patients treated as early as 1987), and ultrasensitive PSA did not become widely available until the 21st century. The authors clearly state,

This observation suggests that SRT at the lowest PSA level is most beneficial for long-term therapeutic efficacy.

Dr. Stish emphasized this point in a note to me:

We chose a PSA cutoff of 0.5 ng/ml to allow comparison with other previously reported studies that have cited this arbitrary point of dichotomy. As you read the paper, you will note that our data suggest salvage radiotherapy is most efficacious when the PSA is lowest, and in general we advocate for SRT to be considered at the earliest detectable values following prostatectomy.

As we have seen in several analyses, early SRT should be considered when the ultrasensitive PSA reaches 0.03 ng/ml (see this link). But “considered” doesn’t mean “chosen.” What is of critical importance is that the patient begin meeting with a radiation oncologist to discuss the many considerations, including positive surgical margins -- their size and Gleason score, stage T3/4, lymph node status, PSA stability, Decipher scores, and possible advanced PET studies to detect distant metastases. If they mutually determine that SRT is appropriate, discussions should include such variables as dose, hypofractionation (if any), pelvic lymph node treatment (if any), and adjuvant ADT type and duration.

 note: Thanks to Dr. Brad Stish for allowing me to review the full text and for answering questions.

Radiation therapy may improve survival even when PSA≥75 ng/ml

Sometimes when patients originally present with very high PSA levels, a negative bone scan, and CT, they are put on permanent hormone therapy because the doctor just assumes it is micrometastatic. A closer look at the data demonstrates that an attempt at curative radiation may improve outcomes.

Lawrence et al. screened the 2004-2008 SEER database, and found 75,539 patients diagnosed with non-metastatic prostate cancer, and excluded those treated with surgery or brachytherapy. The patients had a median age of 70 years. Their findings based on a median of 60 months of follow up were:

• ·      Use of RT was associated with a reduction in prostate cancer mortality of 59%.
• ·      4-yr prostate cancer survival was 94% in those who had RT vs. 77% in matched patients who had no local therapy.
• ·      The benefit held even for those with PSA≥75 ng/ml

Three important caveats:

(1) This is a retrospective study and is subject to selection bias. This means that those who received no local therapy may have done so for reasons not readily apparent in the available records. Although the authors made an attempt to account for age, grade, PSA level, stage and perhaps other variables, there may have been signs of greater progression that the doctor was aware of.

(2) The PSA values recorded in the SEER database have recently been called into question. Interested readers may read more about it here. In fact, the National Cancer Institute has withdrawn PSA data from the current files. This analysis was evidently performed before that withdrawal on April 29, 2015. This does not affect the survival data.

(3)  A median of 60 months of follow up is not long enough to determine whether survival benefits are sustained in the long run. Neither the radiation-treated cohort nor the non-treated cohort reached median survival during the time period of observation so far available.

Given those caveats, we can only conclude that there may be something to this, but that can only be determined by a clinical trial where patients with extremely high PSA levels are randomized to radiation therapy or hormone therapy only, and they are tracked for ten years or more. The study does suggest that PSA alone is not a good risk factor on which to base the decision about whether to pursue curative therapy.

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.