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

Sunday, September 29, 2019

"Adjuvant" similar to "Early Salvage" Radiation Outcome in Meta-analysis

Although at least three randomized clinical trials have told us that adjuvant radiation after prostatectomy often affords better results than just taking a "wait-and-see" approach, most radiation oncologists have been reluctant to immediately treat every man with poor post-prostatectomy pathology results (positive margins, stage T3/4, high Gleason score).  Now, some early combined results (called a meta-analysis) of three more randomized clinical trials suggest that oncological outcomes may be no worse if men wait to be treated until certain PSA cut-offs are reached.

The three randomized clinical trials were RADICALS-RT (UK & Canada), GETUG-AFU-17 (France), and RAVES (Australia & NZ). The meta-analysis, called "ARTISTIC" (critique here). comprised 2151 men, of whom 1074 were randomized to adjuvant radiation and 1077 were randomized to early salvage radiation. There have been 5 years of follow-up so far. ARTISTIC analyzed the early data based on "event-free survival," which for the most part meant freedom from a PSA-defined recurrence after radiation.

"Adjuvant" radiation (ART) was defined by all three trials as treatment within 6 months of prostatectomy. Note that this can be longer than the "immediate" treatment often given.

"Early salvage" radiation (eSRT) was defined variously as treatment when PSA ≥ 0.1ng/ml or 3 consecutive rises (RADICALS-RT), PSA≥0.2 ng/ml and rising (GETUG-AFU-17), or PSA≥0.2 ng/ml (RAVES).

Patients in all three trials had positive surgical margins, extracapsular extension, or penetration into the seminal vesicles. Most patients were intermediate risk:
  • Most (77%) had a Gleason score of 7
  • Very few (9-17%) had a Gleason score of 8-10
  • About 1 in 5 had seminal vesicle invasion

After 5 years of median follow-up:
  • Event-free (mostly PSA) survival was about the same for ART and eSRT (HR=1.1, p=0.47)
  • 57% of patients randomized to SRT never had it because they didn't have biochemical progression

The following are the results for RADICALS-RT (1,496 patients followed up for 4.9 years):
  • 64% of the patients randomized to receive eSRT, never experienced PSA progression
  • At 5 years, biochemical progression-free survival was 85% for ART and 88% for eSRT (p=0.56, not statistically different)
  • At 5 years, freedom from permanent ADT was not different (93% for ART, 92% for eSRT)
  • Urinary incontinence at one year was 5.3% for ART vs 2.7% for eSRT (p=0.008, statistically different)
  • Serious or life-threatening urethral stricture was 6% for ART vs 4% for eSRT (p=0.02, statistically different)

The following are the results for GETUG-AFU-17 (424 patients with 6.3 yrs of follow-up):
  • 41% of the patients randomized to receive SRT, never experienced PSA progression
  • 5-yr event-free survival (no PSA or clinical relapse) was the same (92% for ART, 90% for SRT)
  • Late-term urinary toxicity (any grade) was worse for ART (73% for ART, 29% for SRT)
    • incontinence:  54% for ART, 17% for SRT
    • frequency: 39% for ART, 15% for SRT
  • Late-term rectal toxicity (any grade) was worse for ART (44% for ART, 20% for SRT)
  • Late-term erectile dysfunction (any grade) was worse for ART (36% for ART, 13% for SRT)

The following are the results for RAVES (333 patients with 6.1 yrs of follow-up):
  • 47% of the patients randomized to receive SRT, never experienced PSA progression
  • 5-yr freedom from biochemical relapse was the same (86% for ART, 87% for SRT)
  • Late-term urinary toxicity (grade 2+) was worse for ART (70% for ART, 54% for SRT)
  • Late-term rectal toxicity (grade 2+) was the same (14% for ART, 10% for SRT)

Pelvic lymph nodes

If pelvic lymph node dissection during prostatectomy revealed any positive nodes, or if scans suggest enlarged, cancerous pelvic lymph nodes, there is no question that adjuvant radiation is required. RTOG 0534 showed that salvage radiation of pelvic lymph nodes with adjuvant ADT increase progression-free survival even when there were no detected cancerous lymph nodes, but only if PSA was high enough.

It is never worth waiting for PSA to rise to a point where newer PET scans can detect metastases just to find out where the largest sites of recurrence are. That would be a self-fulfilling prophesy - the goal is curative treatment before the cancer has time to metastasize. A/SRT must be given to the prostate bed, and possibly an extended pelvic lymph node field. The patient must treat what is still too small to see.

Adjuvant ADT

Other arms of RADICALS, not yet reported, explored the effect of various durations of adjuvant hormone therapy. GETUG-AFU-16 proved that adding at least 6 months of ADT improved results of SRT. RTOG 0534 also showed that adding ADT to SRT was often beneficial. But RTOG 9601 showed that adjuvant ADT did not improve results when postprostatectomy PSA was below 0.7 ng/ml. A recent analysis by Spratt et al. suggested that adjuvant ADT is always necessary when PSA ≥ 1.5 ng/ml, but that risks may outweigh benefits when PSA is lower than 0.6 ng/ml.

Radiation Dose

GETUG-AFU-17 and RADICALS-RT used a radiation dose of 66 Gy in 33 treatments. RADICALS-RT also allowed a moderately hypofractionated dose (52.2 Gy in 20 treatments). RAVES used a slightly lower dose: 64 Gy in 32 treatments. A recent analysis by Chris King suggested that these doses may be inadequate, or that a higher dose may not require adjuvant ADT. The effect of the higher dose on toxicity using the best linacs is unknown.

High Risk/Decipher

Most of the men in these trials were originally intermediate risk. It is entirely possible that originally high-risk men (Gleason 8-10, PSA≥20 or cT3/T4) may benefit more from ART rather than eSRT.  Men who were originally low risk (Gleason 6 and PSA<10 and T1/2) may be able to wait longer or indefinitely before SRT.

If the Decipher score is very high, that should also be taken into account in deciding between ART and eSRT. Genome Dx also provides scores that suggest whether the cancer is amenable to SRT, but those scores have yet to be prospectively validated.

We are starting to get a better handle on the ART vs eSRT decision, but none of what we have learned gives us hard-and-fast guidelines. Thee trial results do provide more fodder for discussion between the patient and his radiation oncologist.

Wednesday, January 3, 2018

When can ADT be safely avoided with salvage radiation therapy?

Two randomized clinical trials (GETUG-AFU-16 and RTOG 9601) proved that adding at least some ADT to salvage radiation (SRT) improved outcomes. "Some ADT" was 6 months of goserelin in the GETUG-AFU-16 trial, and two years of bicalutamide in the RTOG 9601 trial. Retrospective studies suggest improved outcomes as well (see this link and this one). On the whole, adjuvant ADT improves SRT outcomes. But is there a subgroup of patients, especially those treated early enough, in whom adjuvant ADT can be safely avoided?

This was the subject of a retrospective analysis by Gandaglia et al. They examined the records of 525 post-prostatectomy patients treated with SRT at six international institutions between 1996 and 2009. Inclusion criteria were:
  • Undetectable PSA (<0.1 ng/ml) after prostatectomy
  • Biochemical recurrence - two consecutive PSA rises above 0.1 ng/ml
  • PSA mostly ranged from 0.2 to 0.9 ng/ml (median 0.4) at the time of SRT
  • No detected lymph node metastases
There were 178 patients who received adjuvant ADT (median 15 months) and 347 who had SRT without ADT. Compared to those who received no ADT, those that did were:
  • Similar in age, initial (pre-op) PSA, and Gleason score
  • More likely to be stage T3b/4
  • Less likely to have positive margins
  • Received higher SRT dose (70 Gy vs 66 Gy)
There were 8 years median follow-up for those who had no ADT, and 12 years median follow-up for those who had adjuvant ADT. The authors compared the actual 10-yr metastasis rate to the predicted 10-yr metastasis rate based on PSA at SRT, Gleason score, stage, positive margins, SRT dose, and whether lymph nodes were treated. They found that:
  • Only those with a 10-year probability of distant metastases greater than 1 in 3 benefited from the addition of ADT
  • The benefit grew exponentially with increasing risk
  • Adjuvant ADT only benefited those with higher PSA (≥0.4 ng/ml), Gleason score 8-10, stage T3b/4. 
  • Higher SRT dose and whole pelvic SRT improved outcomes independently of whether adjuvant ADT was used.
It should be noted that high-dose SRT and whole pelvic treatment were used in a minority of cases, and there is a significant risk of selection bias in this study.

The authors conclude that a higher radiation dose alone may be sufficient to treat many patients with a recurrence detected early enough, but for those with aggressive tumor characteristics, adjuvant ADT will improve outcomes measurably. While this was not proved with a randomized trial, it does suggest that adjuvant ADT will not be necessary in all cases of SRT. Patients who are undecided may wish to have a Decipher genomic classifier done on their prostate tissue to determine their 10-year risk of metastases.

Sunday, July 9, 2017

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

Monday, March 27, 2017

Conflicting messages after surgery for high-risk patients from radiation oncologists and urologists

In spite of the data suggesting that brachy boost has better outcomes for high risk patients, it is being utilized less often and surgery is being utilized more often. After surgery, the high-risk patient is monitored by his urologist (Uro). If the urologist fears a recurrence, he may (1) refer his patient to a radiation oncologist (RO) for adjuvant or salvage radiation therapy (A/SRT), (2) refer his patient to a medical oncologist if he believes the recurrence is metastatic and incurable, or (3) he may continue to monitor the patient. The rate of utilization of A/SRT has been dwindling in spite of three major randomized clinical trials that proved that ART has better outcomes than waiting. If the patient does get to see a radiation oncologist, he may be advised to be treated soon, in conflict with the urologist advising him to wait. This puts the patient in a difficult situation.

Kishan et al. report the results of a survey among 846 ROs and 407 Uros. The researchers sought their opinions about under which conditions they would offer a high-risk post-prostatectomy patient A/SRT. For the purposes of their survey, they defined "adjuvant RT" as radiation given before PSA has become detectable, and "salvage RT" as radiation given after PSA has become detectable. "Early salvage RT" means PSA is detectable but lower than 0.2 ng/ml.

The following table shows the percent of ROs and Uros who agreed with each survey question:

ART underutilized
ART overutilized
SRT underutilized
SRT overutilized

SRT when first PSA is detectable
ART when first PSA is undetectable
Early SRT when first PSA is undetectable
SRT when first PSA is undetectable

Recommend SRT if PSA is:

2+ consecutive rises

Recommend ART if pathology report is adverse:

Positive margin
Extraprostatic Extension (pT3a)
Seminal Vesicle Invasion(pT3b)
Local organ spread (pT4)
Pelvic lymph node (pN1)
Gleason score 8-10
Prefer SRT

Recommend adjuvant ADT with ART if:

Positive margin
Extraprostatic Extension (pT3a)
Seminal Vesicle Invasion(pT3b)
Local organ spread (pT4)
Pelvic lymph node (pN1)
Gleason score 8-10

Recommend whole pelvic A/SRT if:

Positive margin
GS 8-10
No role

In contrast to Uros, ROs are more likely to believe that both ART and SRT are underutilized. Uros believe that are used about right. ROs often see patients too late if they see them at all.

When the first PSA is detectable, both kinds of doctors would recommend SRT. When the first PSA is undetectable, 43% of ROs would recommend ART nonetheless, while only 16% of Uros would recommend ART.

Most of the ROs would treat when they see 2 consecutive rises in PSA, or if the PSA was detectable and under 0.2. Most (54%) Uros would wait until PSA was over 0.2.

Over half the ROs would recommend ART to high risk patients demonstrating any of several adverse pathological features: positive margins, stage T3/4, or positive pelvic lymph nodes. The majority of Uros would not recommend ART to high risk patients with those adverse pathologies.

The majority (65%) of ROs would include adjuvant ADT if there were positive lymph nodes. Uros were less likely to recommend adjuvant ADT based on lymph node involvement and Gleason score.

While most of both groups would have added whole pelvic radiation for patients with positive lymph nodes, 82% of ROs would, but only 64% of Uros.

ROs, knowing that a locally advanced cancer can suddenly become metastatic, and therefore incurable, would like to give A/SRT as soon as possible. Uros, who treat patients for the combined effect of surgery and radiation on urinary and sexual function, would like to wait as long as possible. The patient is caught in the middle of this difficult decision. Some have recommended beginning neoadjuvant ADT at the lowest detectable PSA and extending that time for as long as needed  to give urinary tissues maximum time to heal. Whatever the high-risk patient may eventually decide is in his best interest, he should meet with an RO immediately after surgery to hear both sides of the issue. Uros are blocking access to information that the patient needs.