Lower salvage radiation dose - are outcomes the same?

A large randomized clinical trial, SAKK 09/10, found that a salvage radiation dose of 64 Gy over 32 treatments had equivalent biochemical outcomes compared to 70 Gy over 35 treatments.

They treated 350 patients from 2011 to 2014 at 28 hospitals in Germany, Switzerland, and Belgium. They were treated with either 3D-CRT (44%) or more modern radiation techniques. None had positive lymph nodes. Key patient characteristics were as follows:

• Biochemically recurrent after prostatectomy (median PSA= 0.3 ng/ml)
• Positive margins in 45%
• Gleason score ≥ 8 in 18%
• No detectable tumors

After 6.2 years of follow-up, outcomes were as follows:

• Freedom from biochemical progression (FFBP) was enjoyed by 65% of those who got 64 Gy vs 73% of the 70 Gy group. This difference is not statistically different (p=0.11).
• Local recurrences (only) occurred in 9% of the 64 Gy group vs 2% of the 70 Gy group. This difference is statistically significant (p= 0.005)
• Regional recurrences (only) occurred in 11% of the 64 Gy group vs 17% of the 70 Gy group. This difference is not statistically significant (p= 0.11)
• Distant recurrences (any) occurred in 15% of the 64 Gy group vs 15% of the 70 Gy group.
• In an earlier report, acute urinary toxicity of Grade 2 or greater occurred in 14% of the 64 Gy group vs 18% of the 70 Gy group (not different)
• In an earlier report, acute rectal toxicity of Grade 2 or greater occurred in 17% of the 64 Gy group vs 18% of the 70 Gy group (not different)
• Late urinary toxicity of Grade 2 or greater occurred in 29% of the 64 Gy group vs 30% of the 70 Gy group (not different)
• Late rectal toxicity of Grade 2 or greater occurred in 12% of the 64 Gy group vs 22% of the 70 Gy group (different)
• Patient-reported outcomes were not different between the two dose regimens.

Oncological Outcomes

The stated purpose of SAKK 09/10 was to detect a difference in 6-year FFBP, and they detected no difference. But is that enough to change practice? The ICECAP working group cautions  that 5-year metastasis-free survival, but not biochemical recurrence-free survival, is a good surrogate endpoint when overall survival would take too long to obtain in trials of primary therapy for localized prostate cancer. For trials of salvage therapy of recurrent prostate cancer after prostatectomy, some early analysis suggests that the 5-year occurence of distant metastases may be a good surrogate endpoint. 6-year FFBP used in this trial is probably not a good surrogate endpoint.

Focusing our attention on the actual cancer progression instead of just PSA progression, we see that the higher dose did significantly better at preventing local progression of the cancer. If the trial were to run 15 years, we might see a very meaningful difference between the curative powers of the two dose regimens. Furthermore, as shown in the SPPORT trial, salvage treatment of pelvic lymph nodes, even when none is detectable, may slow progression or possibly cure some patients with regional micrometastatic progression. 

There may be other ways to improve outcomes:

• Using the expanded prostate bed delineation guidelines may improve local control.
• As PSMA PET/CT becomes more widely available, it will be possible to detect more loco-regional cancer for boost doses, and eliminate salvage treatment from patients who already have small distant metastases (see this link). 
• The use of genomic tests, like Decipher Genomic Classifier (GC), may aid in selecting patients in whom higher doses are needed. In a subset analysis, among Decipher "high GC-risk" patients, FFBF was 51% for 70 Gy vs 39% for 64 Gy patients; among Decipher "low GC-risk" patients, FFBF was 75% for 70 Gy vs 69% for 64 Gy patients (update) FFBF was 45% for GC-high patients vs 71% for GC-low patients. 
• There is a clinical trial at UCLA that will determine whether raising the biologically effective dose (BED) using SBRT (34 Gy/ 5 fractions) gives good outcomes compared to historical controls. The BED is equivalent to 85 Gy if given in fractions of 1.8 Gy.
• There is a clinical trial in France that will determine whether adjuvant hormone therapy intensification with Erleada improves results.
• Keeping in mind that very few patients in this trial had Gleason scores of 8-10, and none had detectable gross tumors at or near the prostate, those patients may still be good candidates for dose intensification (as well as adjuvant ADT).

Toxicity Outcomes

If there is no cost to the patient in terms of increased toxicity, there is no reason not to increase the dose. The patients were unable to detect a difference in urinary, rectal, or sexual outcomes. There was a difference in physician-reported late-term rectal toxicity that deserves further attention.

Compared to acute urinary toxicity, late-term urinary toxicity is about twice as bad in both dosing regimens, although the ratings are not different between regimens. Compared to acute rectal toxicity, late-term rectal toxicity was 29% lower for the 64 Gy dose group, but marginally higher for the 70 Gy dose group. The authors believe that rectal dose constraints could be tightened with IMRT.

For comparison, MSK reported that using 70 Gy as a salvage dose, late-term urinary toxicity (Grade≥2) was 17% (vs 30% in this trial) and late-term rectal toxicity (Grade≥2) was 5% (vs 22% in this trial). They also reported that IMRT improved rectal toxicity over 3D-CRT, while no difference was observed in this trial.

The reason for these atypical results is mysterious, although physician-reported toxicities are notoriously unreliable.

So, lacking more reliable endpoints and considering that patients did not notice any difference in their quality of life based on dose intensification, the decision on what dose to use is best based on a discussion with the radiation oncologist.

(update 04/22/2022) Beck et al. report that adherence to treatment guidelines was poor in the SAKK 09/10 trial. This may explain the mysterious toxicity results as well as being responsible for worse freedom from biochemical progression.

Salvage Radiation Dose: Decision-Making Under Uncertainty

A large, well-done, confirmed randomized clinical trial (RCT) is the only evidence that proves that one therapy is better than another. According to current consensus, this is deemed "Level 1a" evidence. But this high level of evidence is seldom available. This is especially true of prostate cancer because it takes so long to achieve acceptable endpoints like overall survival, prostate cancer-specific survival, and metastasis-free survival. Such studies are very expensive and difficult to carry out.

Alexidis et al. analyzed the National Cancer Database for men treated with adjuvant or salvage radiation therapy (SRT) after prostatectomy failure from 2003 to 2012. SRT with doses above 66.6 Gy were labeled "high dose," and SRT with doses above 70.2 Gy were labeled "very high dose." Between 2003 and 2012:

• High dose SRT utilization increased from 30% to 64%
• Very high dose SRT utilization increased from 5% to 11%
• Utilization of high and very high dose rates was greatest at academic centers, lowest at community centers.

The authors decry the fact that this doubling of high dose SRT took place in the absence of RCTs that would definitively establish proof. They point out that the evidence for it is based on observational studies (see, for example, King and Kapp and Ohri et al.), which are fraught with confounding due to stage migration,  selection bias and ascertainment bias. Stage migration was the result of better imaging becoming increasingly available to rule out SRT from patients already harboring occult distant metastases. Also, three randomized clinical trials published in the middle of the observational period convinced many radiation oncologists that earlier SRT led to better tumor control than waiting. Selection bias occurred because the patients selected to get higher doses of radiation were healthier and those whose cancer was less progressed -- they would have done better regardless of the dose. Ascertainment bias resulted from the longer observational period for patients treated in 2003 vs. 2012 - the opportunity for treatment failure increases with the amount of time that has passed. The authors also doubt that biochemical recurrence-free survival (which is what was used in observational studies) is a good enough surrogate endpoint for overall survival. They are right that all these factors may be confounding the previous retrospective analyses, and the only way to know with certainty is to conduct a trial where patients are randomized to receive high or low SRT doses,  and follow patients long enough so that median survival or at least metastasis-free survival is reached in the low dose group.

There has been one randomized clinical trial of SRT dose escalation in the modern era. The SAKK 09/10 trial found little difference in acute toxicity symptoms at 70 Gy compared to 64 Gy, but patient-reported urinary symptoms worsened. Unfortunately, many patients were treated with three-dimensional conformal radiation therapy (3D-CRT), which had higher toxicity than the IMRT in widespread use now. Also, it uses freedom from biochemical failure (not yet reported) as its surrogate endpoint.

So, what is a patient to do in the absence of Level 1a evidence? Should he accept the higher doses with possibly added toxicity and better tumor control, or should he go for a lower dose with possibly less toxicity and less tumor control?

As a compromise, Mantini et al. recently reported 5-year biochemical disease-free survival (bDFS) and other outcomes for patients who received higher dose SRT (70.2 Gy vs. 64.8 Gy) depending on their post-operative pathology. They also may have received (depending on pathology) whole pelvic radiation and adjuvant hormone therapy. Those patients who received the higher dose had equivalent 5-yr bDFS in spite of their worse disease characteristics. Those who received only 64.8 Gy still had a 5-year bDFS as high as 92%. We do not know how many of those recurrent men with favorable disease characteristics actually needed any SRT. They were all treated with 3D-CRT and toxicity was not reported.

The other thing we can do when our information is imperfect is go through the Bradford Hill checklist. It can give us more confidence if we have to make a decision based on less than Level 1 evidence. The factors that ought to be considered are:

• Strength of Association (larger associations are more likely (but not necessarily) causal)
• Consistency of Data (independent studies all lead to the same conclusion)
• Specificity (a very specific population is differentially affected)
• Temporality (the effect has to occur after the cause)
• Biological gradient (too some extent, more drug/radiation dose leads to more effect) 
• Plausibility (one can come up with a plausible explanation)
• Coherence (lab studies demonstrate a plausible mechanism for the observed effect)
• Experiment (has the effect been prevented by modifying the cause)
• Analogy (similar factors may be considered)

Unfortunately, the authors did not refer to Dr. King's more recent analysis of SRT dose/response, which we discussed in depth here. He looked at 71 studies, demonstrating consistency. While it is not Level 1 evidence, it is Level 2a evidence. In it, he observes that the salvage radiation dose response conforms exactly to the primary radiation dose response.  In other words, the prostate tumor is equally radio-resistant whether it is in the prostate or the prostate bed. This increases the plausibility of a dose effect of SRT. What's more, dose escalation was proven to be beneficial for biochemical recurrence-free survival, metastasis-free survival, and freedom from lifelong ADT use, for primary radiation in intermediate risk men by a RCT (RTOG 0126). So, we also have greater confidence in SRT dose escalation by analogy.

RTOG 0126 did not find an increase with higher dose in 8-year overall survival or cancer-specific survival. This calls into question whether these longer-term effects are really useful endpoints if we are to be able to obtain and use the results of any clinical trial in a reasonable time frame.

Dr. King proposed a randomized clinical trial of 76 Gy vs. 66 Gy for SRT. Meanwhile, he is routinely giving his SRT patients at UCLA 72 Gy. Dr. Zelefsky at Memorial Sloan Kettering Cancer Center and other eminent radiation oncologists have also upped the radiation dose to 72 Gy. Such doses seem to be safe and effective, but it is one of many factors in the SRT treatment decision that must be carefully considered by patients and their doctors.

A PSMA-based PET scan can change salvage radiation treatment decisions

The new PSMA-based PET scans provide a way to locate exactly where the cancer has spread to after an unsuccessful prostatectomy. Formerly, the only tools we had were scans that could only detect very large or rapidly growing tumors at PSAs well above the levels most radiation oncologists would be comfortable treating with salvage radiation; that is, there is widespread agreement that success rates improve the lower the PSA is when SRT is used. Even the newly approved Axumin PET scan only detects cancer in 38% of patients if their PSA is in the range of 0.2-1.0 ng/ml. By contrast, as we saw recently, the Ga-68-PSMA-11 PET scan has detected cancer in half of men when their PSA was still below 0.2, and in about two-thirds of men whose PSA was 0.2 - 0.4. The PSMA-based PET scan has the power to change SRT treatment decisions.

Calais et al. reported the results of a multi-institutional study of the Ga-68-PSMA-11 PET/CT in 270 men with biochemically recurrent prostate cancer after prostatectomy while their PSAs were still below 1.0 ng/ml (median 0.44). The institutions comprised UCLA, Technical University of Munich, Ludwig-Maximillian University of Munich, and University of Essen. Patients received PET scans from 2013-2017. Researchers painstakingly mapped all sites of cancer to find the locations of cancer that would have been missed if they had just blindly treated the prostate bed and/or the pelvic lymph node field recommended by RTOG guidelines.

The following table shows how treatment decisions might change based on their findings.

So, all in all, about half of treatment decisions might change - 30% in a minor way, 19% in a major way. The major changes would be: 

• forgoing SRT entirely in up to 12%
• consider metastasis-directed radiation in 8% - a treatment of unknown significance
• changing from prostate bed-only to whole pelvic SRT in 11%, so as to potentially render curative what would have been a non-curative treatment
• expanding the pelvic treatment field in 7%, so as to potentially render curative what would have been a non-curative treatment

At the above institutions, extended pelvic lymph node dissection (ePLND) is common practice - 81% of patients had a PLND. Consequently, 20% of patients already had detected pelvic LNs (N1) before the scan. At many institutions in the US where ePLND is less common in intermediate and high risk patients, this can cause a much larger and potentially curative change in the treatment plan from prostate bed-only to whole pelvic radiation. The researchers are to be congratulated for the painstaking work in contouring and comparing so many pelvic scans.

As one might expect, PSMA-based cancer detection was higher for those with Gleason score more than 7, and those with pathological stage N1 and T3. The patient's PSA at the time of the scan played a major role. While almost two-thirds had a PSA ≤ 0.5 ng/ml, the detection rate was 41% for those patients vs. 60% for those with higher PSAs. While detection improves with higher PSA, it is important for patients to understand that it is unwarranted (and potentially unsafe) to wait for PSA to rise just so that more cancer can be detected. That would be a self-fulfilling prophecy: by waiting for the cancer to put out more PSA, one is virtually ensuring that the cancer will grow, spread, and possible metastasize. Although we await definitive clinical trial data, most radiation oncologists recommend early treatment (before PSA reaches 0.2 ng/ml) for men with adverse pathology or for those evincing a distinct pattern of PSA progression after prostatectomy.

While a previous analysis showed that the Ga-68-PSMA PET had little effect on SRT decisions, and no patients were upgraded from incurable to potentially curable, this larger, more detailed study indicates that about 1 in 5 patients can be upgraded, and 1 in 6 can be spared SRT. This would seem to justify the cost. UCLA charges $2650 for recurrent (and high risk) patients. NIH is recruiting recurrent and high risk patients for an improved PSMA-based PET scan (called DCFPyL) that  is free (and transportation to Washington D.C. is covered as well).

New Study: Adjuvant Radiation Saves Lives vs. Salvage

A major new study adds to several other studies that show that, for men with adverse pathology, adjuvant radiation (ART) within 3-6 months of prostatectomy saves more lives compared to waiting until the PSA rises into the range of 0.1-0.5 ng/ml - salvage radiation (SRT).

Three previous randomized clinical trials have shown an advantage to adjuvant radiation over a "wait-and-see" approach. However, only one of them (SWOG  S8794) showed that there was an improvement in freedom from metastases and overall survival attributable to earlier treatment. That study was limited in its generalizability because only a third of the "wait-and-see" cohort ever received salvage radiation. ARO-96-02 was designed to detect differences in progression-free survival (which were significant), but it was underpowered to detect overall survival differences. EORTC 22911 was designed to detect differences in progression-free survival (which were significant), but although it had a larger sample size, overall survival did not improve. Sub-group analysis showed the survival benefit was limited to men under the age of 70. A recent meta-analysis of the three trials showed that freedom from biochemical failure, freedom from life-long ADT,  and freedom from distant metastases were significantly improved by adjuvant treatment. But less than half of the men in the wait-and-see arms ever received salvage radiation, and 20-40% of  them never suffered a recurrence. All three trials used salvage radiation doses that would now be deemed too low. ART utilization rates are at an all-time low of 17% in men with adverse pathology.

What we really want to know is: what is the downside of waiting until the PSA rises to some arbitrary level, say 0.2 ng/ml? That is the subject of three randomized clinical trials, but we will not have the findings for several years. Meanwhile, some researchers looked at historical data in a new way to determine whether there is any evidence that might aid in decision-making.

Hwang et al. have pooled the databases from ten top institutions: Massachusetts General, Cleveland Clinic, University of Michigan, Duke University, Washington University, Mayo Clinic, University of Chicago, University of Miami, Virginia Commonwealth University, and Thomas Jefferson University. There were 1,566 patients who were treated between 1987-2013. Patients either had fully contained prostate cancer (T2) with a positive margin or extraprostatic extension (T3a)/ seminal vesicle invasion (T3b) with or without a positive margin.

They used a statistical technique called "propensity score matching" that in some respects resembles what would have resulted from a prospective randomized trial. Every patient who had ART was matched, in terms of patient characteristics, to a patient who had SRT. Patients are chosen randomly from among those with matched characteristics.  Patients were matched on age at surgery, year of surgery, Gleason score, T stage, margin status, postoperative ADT, and pelvic nodal RT. In this way, they were able to generate 366 matched pairs of patients. This technique works quite well in predicting outcomes of prospective randomized trials as long as there is a large enough sample size, considerable overlap in patient characteristics (which there was) and there aren't any prognostic patient characteristics that were missed.

The researchers found that all measured outcomes were significantly better among those who received ART:

• 12-year freedom from biochemical failure: 69% for ART vs. 43% for SRT
• 12-year freedom from distant metastases: 95% for ART vs. 85% for SRT
• 12-year overall survival: 91% for ART vs. 79% for SRT
• Patients who suffered biochemical failure were more likely to have had SRT, have been stage T3b, have had higher Gleason score, had not been treated with lymph node radiation, and had not had postoperative ADT.
• The advantage of ART was only lost if more than 56% of them would have been overtreated, but based on nomograms, no more than 46% would have been overtreated (using the assumption that 2/3 were GS 3+4 and 1/3 was GS 4+3).

Pending confirmation by the randomized clinical trials, this study is our best evidence to date that ART is preferable to SRT. However, there are a few very important caveats:

• They defined SRT as treatment when the PSA is in the range of 0.1 - 0.5 ng/ml. (They actually call this "early" salvage -- a term I would prefer to reserve for radiation when the ultrasensitive PSA (uPSA) is below 0.10 ng/ml.) For uniformity reasons in this 10-institution study, any PSA below 0.10 ng/ml on an uPSA test was deemed "undetectable," and those treated at very low PSAs were considered to have had ART. They had to use those definitions in their analysis because of the heterogeneous data set with PSAs recorded as early as 1987 (before there were any ultrasensitive PSAs). Because the risk of overtreatment with ART is high (they estimate 33%-52%), it behooves patients to track their post-prostatectomy PSA with an ultrasensitive test. We have seen that for men with adverse pathology,  any uPSA over 0.03 ng/ml reliably predicts that it will keep going up to 0.2 ng/ml (see this link). In men without adverse pathology, only a convincing pattern of PSA rises is prognostic.
• Adverse pathology in this study included anyone with positive margins, but others advocate that the length of the positive margin and the Gleason score at the margin are important considerations. A patient with focal positive margins and GS 6 at the margin may never need additional ART or SRT.
• They lumped together men whose PSA was undetectable but then climbed higher and men whose PSA was persistently elevated after prostatectomy. Persistent PSA with adverse pathology is a clearer indicator that gross amounts of cancer were left behind and calls for some quick action.
• The Decipher genomic test was not available throughout most of the study period. For those sitting on the fence, it may be a decisive factor.
• The newer PET scans (Axumin and PSMA-based) can find metastases if PSA is greater than 0.2 ng/ml. Multiparametric MRI may be able to find sites in the prostate bed or among the pelvic lymph nodes where tumor size is longer than 4 mm. Because of the advantage of earlier treatment, most men will require treatment before metastases become detectable. Some will be overtreated if the cancer is already systemic.
• Among very high risk patients (i.e., GS 8-10, seminal vesicle invasion (T3b) or invasion of nearby organs (T4), and very high persistent PSA) the probability that ART or SRT will be curative may be very low. Patients should understand what the population-based risk is from a nomogram.
• The radiation doses delivered were at a median dose of 66 Gy. More recent evidence suggests that higher doses may be necessary to achieve a cure. The value of adjuvant ADT and whole pelvic radiation suggested here has also been suggested by a number of other studies.
• This study excluded patients with detected positive lymph nodes. That is a clear indication for ART.

There are many factors to consider including comorbidities, continence and potency recovery. This will seldom be a straightforward decision. Patients with adverse pathology and uPSA over 0.03 ng/ml should be talking to a radiation oncologist and not a urologist.

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.

Salvage whole pelvic radiation after cancerous pelvic lymph nodes have been found

Is it still worthwhile to attempt salvage radiation (SRT) after positive pelvic lymph nodes (PLN) have been pathologically detected (stage pN1)? Traditionally, patients with PLN dissection (PLND)-diagnosed pN1 prostate cancer have been considered to have incurable systemic disease. Therefore, they were either observed until distant metastases were identified or started on lifelong androgen deprivation. Retrospective studies of the benefit of salvage whole pelvic SRT for pN1 patients have been equivocal: Abdollah et al. and Rusthoven et al. showed a benefit to salvage RT, but Kaplan et al.showed no benefit.

(Update 9/25/2022) Fonteyn et al. reported the results of the first randomized clinical trial, the PROPER RCT. Unfortunately, the trial did not reach its recruitment targets (n=64) and follow-up was shorter than planned.

• All patients had 1-4 positive PLNs found via PLND, most had 1 positive PLN
• Most (75%) also had prostatectomy, 64% had positive surgical margins

Patients were randomized to 2 years of ADT and either:

• Whole pelvic RT (as high as common iliac LNs) (WPRT), or
• Prostate bed-only RT (boost dose was allowed for known sites of recurrence) (PORT)

After 3-years of follow-up:

• Biochemical recurrence-free survival was 92% for WPRT vs 79% for PORT
• Acute grade 2+ gastrointestinal (GI) toxicity was 45% for WPRT vs 15% for PORT
• Late-term grade 2+ gastrointestinal toxicity was 21% for WPRT vs 3% for PORT
• Acute grade 2+ urinary toxicity was 52% for WPRT vs 48% for PORT (no diff.)
• Late-term grade 2+ urinary toxicity was 41% for WPRT vs 42% for PORT (no diff)

GI toxicity was probably increased by the wide margins used (5 mm) and by the fact that radiation was given on top of surgically dissected tissue. Such extended PLND is rarely done outside of Europe. The SPPORT and POP-RT trials, which did not include previous PLND, found no increase in GI toxicity. Now that PSMA PET/CT is available for recurrent patients, toxicity will probably be lower. The new MRI-targeting linacs (Viewray MRIdian and Elekta Unity) can control for intestinal motion that causes toxicity. Also, there may be an opportunity for better oncological results if para-aortic lymph nodes are also treated (see this link). A STAMPEDE trial found that 2 years of abiraterone increased oncological results.There may also be an opportunity to enhance results with apalutamide.

In an analysis of the National Cancer Database of 7,791 prostatectomy patients (treated from 2003-2010) who were staged pN1 after PLND, Zareba et al. found that most (63%) were initially observed without treatment, and an additional 20% received androgen deprivation (ADT)-only within a year of diagnosis. Only 18% received SRT, most of those (72%) with adjuvant ADT. Those treated with whole pelvic SRT+ADT had worse disease characteristics than those who were observed only: higher Gleason score, higher stage, higher positive surgical margin rate, and greater number of positive lymph nodes.

After 5.9 years median follow-up on 3,680 patients:

• Treatment with whole pelvic SRT+ADT decreased 10-yr mortality by 31% compared to observation only, and by 35% compared to ADT-only.
• Treatment with ADT-only or SRT-only was not associated with an increase in survival

Touijer et al. reported on 1,388 pN1 patients treated at three top institutions: Memorial Sloan Kettering (MSK), the Mayo Clinic, and San Raffaele Hospital in Milan. The MSK cohort was primarily only observed, the Mayo cohort primarily received lifelong ADT-only, and the Milan cohort was primarily treated with whole pelvic SRT+ADT As in the Zareba study, SRT+ADT patients had worse disease characteristics.

After 5.8 years median follow-up:

• Treatment with whole pelvic SRT+ADT decreased 10-yr mortality by 59% compared to observation only, and by 54% compared to ADT-only.
• Those with worse disease characteristics benefited the most.
• Treatment with ADT-only was not associated with an increase in survival compared to observation, although prostate cancer-specific survival was increased.

Zareba and Touijer did not report the toxicity of the salvage treatment, but with improved external beam radiation techniques and scrupulous image guidance, toxicity has been improving.

Zareba and Touijer had very similar outcomes. Although they were both retrospective studies rather than prospective randomized trials, it should be noted that the selection bias that typically plagues retrospective studies favored those who did not receive SRT+ADT. In spite of their worse disease characteristics, the patients who received pelvic SRT+ADT survived longer.

Recently we saw a similar advantage to pelvic SRT+ADT even in men who were not diagnosed as stage pN1 with a PLND (see this link). Taken together, these studies indicate a marked survival advantage to treating the whole pelvic area in men with pathologically diagnosed high-risk prostate cancer post-prostatectomy. A previous study found that among men with pN1, the ten-year incidence of distant metastases was 35%, suggesting that spread may be confined to pelvic lymph nodes for some time. This creates a unique window of opportunity during which salvage treatment may still be curative.

We have also seen evidence that high-risk patients with imaging-detected positive lymph nodes benefited from whole pelvic radiation as primary therapy (see this link).

These studies also constitute better evidence than we currently have that whole pelvic radiation with ADT is a better idea than picking off lymph nodes one at a time (for which we have no evidence of survival benefit). As we have seen (see this link), our ability to detect all cancer-infected lymph nodes is poor.

There are several variables that the patient and doctor must decide upon, and for which there is no clear evidence: duration of adjuvant ADT, amount of radiation, and the pelvic lymph node field. Clinical trials show that at least 6 months of adjuvant ADT with SRT even without lymph node involvement increases oncological effectiveness, the optimal duration is unknown and may vary with disease characteristics (see this link). The amount of radiation to the pelvic lymph node field seems to be about 50 Gy in most cases, and the amount given simultaneously to the prostate bed will ideally be at least 70 Gy (see this link). The extent of the treated area has been questioned recently. Studies show that infected lymph nodes are often missed in the common iliac area (see this link). There will be variations due to individual anatomy and known bowel sensitivity.

(Update 4/25/21) A major Phase 3 randomized clinical trial (INNOVATE) in 141 locations will determine whether intensifying the hormonal side of the treatment with 2 years of Zytiga+Erleada+ADT has better outcomes than 2 years of ADT. They prefer detection with an Axumin scan but allow PSMA and C-11 Choline too. The whole pelvic radiation dose will be determined by the treating radiation oncologist.

Questions for an adjuvant or salvage radiation doctor

Questions for a Adjuvant or Salvage Radiation Interview.

1. How many prostate cancer patients have you treated with adjuvant/salvage radiation?

2. How has your practice of salvage treatment changed, if at all?

3. Is there any kind of scan that you recommend to rule out metastases that might be useful at my current PSA?

4. What is the probability that I need salvage treatment? Do you calculate that from a nomogram?

5. Do you think I should get a Decipher test to find my probability of metastasis in the next 5/10 years? Do you know if my insurance covers it? What do you think about their PORTOS score?

6. How large a dose do you propose for the prostate bed? (should be near 70 Gy -72 Gy)

7. Do I need pre-treatment, concurrent or adjuvant ADT?

     a. Why?

     b. What's the evidence that it's useful?

     c. For how long?

8.How do you decide whether to treat the pelvic lymph nodes?

     a. If so, at what dose?

     b. How do you plan to prevent bowel toxicity?

     c. How will you account for the separate movement of that area and the prostate bed?

9. What do you think of doing this in fewer treatments (hypofractionation)?

10. What kind of machine do you use? (e.g., RapidArc, Tomotherapy, etc.) Why do you prefer that one?

11. What is the actual treatment time for each treatment? (faster is better)

12. What kind of image guidance do you propose? fiducials in the prostate bed? Using the fixed bones only? Soft tissue?

13. How will inter- and intra-fractional motion be compensated for?

14. What measures do you propose to spare the bladder and rectum?​ (ask about treatment margins and dose constraints)

15. What side effects can I reasonably expect, and how do we handle them?​(discuss in detail!)

16. What probability of a cure can I reasonably expect, given my stats? Is there a nomogram you use to come up with that?

17. How will we monitor my progress afterwards, both oncological and quality of life?

18.What's the best way for us to communicate if I have a question or issue?

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:

	RO	Uro
ART underutilized	75%	38%
ART overutilized	4%	19%
SRT underutilized	65%	43%
SRT overutilized	1%	5%
SRT when first PSA is detectable	93%	86%
ART when first PSA is undetectable	43%	16%
Early SRT when first PSA is undetectable	42%	43%
SRT when first PSA is undetectable	16%	41%
Recommend SRT if PSA is:
Detectable	15%	7%
2+ consecutive rises	30%	20%
>0.03-0.1	8%	8%
>0.1-0.2	13%	11%
>0.2-0.4	29%	35%
>0.4	5%	19%
Recommend ART if pathology report is adverse:
Positive margin	80%	47%
Extraprostatic Extension (pT3a)	60%	32%
Seminal Vesicle Invasion(pT3b)	68%	47%
Local organ spread (pT4)	66%	46%
Pelvic lymph node (pN1)	59%	29%
Gleason score 8-10	20%	20%
Prefer SRT	12%	25%
Recommend adjuvant ADT with ART if:
Positive margin	14%	12%
Extraprostatic Extension (pT3a)	15%	11%
Seminal Vesicle Invasion(pT3b)	29%	25%
Local organ spread (pT4)	36%	37%
Pelvic lymph node (pN1)	65%	46%
Gleason score 8-10	46%	28%
No ADT	22%	31%
Recommend whole pelvic A/SRT if:
Positive margin	6%	9%
EPE	12%	9%
SVI	25%	22%
pT4	30%	30%
pN1	82%	64%
GS 8-10	36%	24%
No role	12%	24%
Other	13%	3%

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.