The definition of SECOND biochemical recurrence (after prostatectomy AND salvage radiation)

There is no standard definition of SECOND biochemical (PSA-detected) recurrence (BCR); that is, after both prostatectomy and salvage radiation (SRT). There are two reasons to have a standard definition of second BCR:

1. Time for next treatment: BCR (after any treatment) is the first indicator of treatment failure, and a signal that it may be time to consider additional treatment. It is not at all clear that immediate additional treatments are beneficial. If a treatment becomes the standard of care after biochemical failure, then it will be necessary to define the PSA or PSA doubling time (PSADT) at which that treatment should begin.
2. Comparison among radiation protocols: Lacking randomized clinical trials among all the variables of when and how salvage radiation are given (pathological characteristics, PSA, PSADT, radiation dose, adjuvant ADT, prostate bed radiation, radiation of pelvic lymph nodes), we can only look at effectiveness across studies to help us hypothesize that one strategy might be better than another. It helps if we have a consistent definition of success.

Miyake et al. looked at three definitions of second BCR:

1. NARA definition: PSA never falls below 0.2 ng/ml; or, it falls below 0.2 ng/ml but later rises over it in two consecutive readings.
2. RTOG 9601 definition: any post-SRT PSA over 0.5 ng/ml; or, nadir + 0.3 ng/ml; or the start of hormone therapy.
3. GETUG definition: nadir + 0.5

They evaluated 118 patients using the 3 definitions. With 49 months of median follow-up after salvage radiation:

• The Nara definition had the highest rate of second BCR; 53%, 45% and 40% for Nara,  RTOG and GETUG respectively.
• Gleason score and Pre-SRT PSA independently predicted Nara BCR, while negative margins and PSADT also predicted RTOG and GETUG BCR.
• There were no discrete cut-offs of the patient characteristics that reliably predicted BCR by any definition

It's worth noting that the definitions may differ for study entry and endpoint (it is usually called "biochemical progression" when used as an endpoint). Many clinical trials use the 0.2 ng/ml definition for the second BCR too.  This trial used PSA≥ 0.2 ng/ml or 3 consecutive rises after RP or SRT. We recently saw that another RTOG trial, the SPPORT trial, used a BCR endpoint definition of nadir + 2 because it correlated well with clinical recurrence. This is the definition advocated by PCWG2.

It is sometimes necessary to define a THIRD BCR as an endpoint to determine whether a therapy that began after a second BCR was successful. For example, an ongoing trial of hormonal therapies for SRT-recurrent men uses a second BCR definition of PSA > 0.5 ng/ml and PSADT ≤ 9 months, and a third BCR definition of a confirmed 25% rise in PSA and nadir + 2 during therapy, and a fourth BCR definition of a confirmed PSA > 0.2 after hormonal therapy.

The definition for FIRST BCR of a confirmed PSA after prostatectomy of 0.2 ng/ml was an artifact of the current lowest discernible PSA before the 21st century, which was 0.1 ng/ml at the time. The American Urological Association decided that anything higher than that would be deemed a BCR. The "ARTISTIC" meta-analysis established that for most patients, it was unnecessary to establish a PSA for first BCR below 0.1 or 0.2.

BCR is just one of a number of elements to be evaluated after SRT. A BCR with a high Decipher score may suggest that immediate salvage ADT is appropriate. With the new generation of PET scans, which can detect metastases at low PSAs, it may sometimes be beneficial to treat pelvic lymph node metastases and possibly distant metastases if SRT had only included the prostate bed.

This small, retrospective study will not establish a new definition, but it does raise the interesting question of whether we need a standard definition, or whether the definition ought to depend upon the purpose for which it is used. If we have definitive evidence that early treatment after failed SRT is beneficial, that will force researchers to investigate the optimum PSA (or PSADT) cutpoint. Until then, the PCWG2 definition (PSA≥ nadir + 2.0), PCWG3 definition (PSA≥nadir+ 1.0), or the combination of PSA and PSA doubling time used in the EMBARK protocol (PSA≥1 and PSADT≤ 9 months) or the PRESTO protocol (PSA≥0.5 and PSADT≤ 9 months) are all reasonable.

PSMA PET finds more cancer than Axumin

A PSMA PET scan (Ga-68-PSMA-11) detected more sites of cancer than an Axumin PET scan in the same recurrent patients. This prospective clinical trial was  conducted among 50 men at UCLA in 2018. All men had post-prostatectomy PSA from 0.2- 2.0 ng/ml.  The Calais et al. findings are summarized in the following table:

	Ga-68-PSMA-11	Axumin
Detected - % of patients	56%	26%
Prostate bed	14%	18%
Pelvic lymph nodes	38%	8%
Extra-pelvic lesions	16%	0%

The two scans performed equally well at detecting recurrence in the prostate bed, but the PSMA PET scan was able to detect more cancerous pelvic lymph nodes and non-regional metastases. The surprising result is that more recurrences are attributable to pelvic lymph nodes (stage N1) or to extra-pelvic metastases (stage M) than to cancer in the prostate bed. If this is true of all recurrent men, it indicates that salvage whole pelvic radiation is usually preferred over salvage prostate bed radiation. We saw (see this link) that salvage whole pelvic radiation improved progression-free survival compared to salvage prostate bed-only radiation. But in that SPPORT trial, the authors noted that the improvement did not hold up at low PSAs. Even the best PSMA PET/MRI has a tumor size detection limit of about 4 mm. If cancer in the pelvic lymph nodes is still curable, it may be necessary to treat cancer while it is still undetectable.

The detection rate by PSA was as follows, but is based on small numbers of patients in each PSA group. The differences in the detection rates are statistically significant for PSAs over 0.5:

PSA (ng/ml)	Ga-68-PSMA-11	Axumin
0.2-0.5 (n=26)	46%	27%
0.51-1.00 (n=18)	67%	28%
1.01-2.00 (n=6)	67%	17%

The other PSMA-based PET scan, DCFPyL, has completed recruiting.

(update 12/19/20) In a meta-analysis - in different patients - the detection rates were as follows:

PSA (ng/ml)	Ga-68-PSMA-11 n = 3,217 in 38 studies	Axumin n = 482 in 6 studies
0.2-0.5	45%	37%
0.51-1.00	59%	48%
1.01-2.00	80%	62%

The difference for PSAs from 1-2 ng/ml is statistically significant.

FDA has approved the Ga-68-PSMA PET/CT at UCLA and UCSF.

One large "zap" for painful bone metastases is enough

In 2011, the American Society for Radiation Oncology (ASTRO) issued a consensus statement as part of its "Choosing Wisely" campaign that found that 30 Gy in 10 fractions (treatments), 20 Gy in 5 fractions, and 8 Gy in 1 fraction all gave equivalent pain relief. The detailed guidelines are here. They did note, however, that repeat treatments were sometimes necessary. A retrospective study this year at the Mayo Clinic found that local control of prostate cancer bone metastases was much improved (from 47% 3-year local control to 87% 3-year local control) by increasing the radiation single dose from 8 Gy to ≥ 18 Gy. (However, the higher dose did not significantly affect the biochemical failure or distant failure rate.)

Now, Nguyen et al. report the results of the first prospective randomized clinical trial. The trial was conducted at MD Anderson from 2014 to 2018 among 160 people with painful bone metastases from any of a variety of cancer types.

• Half received 12 Gy in a single fraction for ≥ 4 cm bone lesions, or 16 Gy in a single fraction for < 4 cm bone lesions (Single Fraction Cohort - SF)
• Half received 30 Gy in 10 fractions (Multi-Fraction Cohort - MF)
• Treated bone metastases were predominantly non-spinal
• Up to three bone metastases were treated at a time

At all follow-up times (2 weeks, 3 months, 6 months and 9 months):

• Pain palliation (complete+partial) was significantly better among the SF
• At 9 months, pain palliation was 77% for the SF vs 46% for the MF
• In the Single Fraction Cohort, those who got the 16 Gy dose had 3 times better pain palliation vs those who got the 12 Gy dose.
• Local control at 2 years was 100% for SF vs 76% for MF
• Median survival was not significantly different
• No significant differences in toxicity (nausea, vomiting, fatigue, dermatitis, and fracture)
• No significant differences in quality of life

This Phase II study was too small to be definitive, especially for cancer-type subgroups. However, the patient should challenge an radiation oncologist who plans to give more than a single fraction to explain his recommendation. (It is entirely possible the the location of the bone metastasis calls for a lower dose rate.) Moreover, the single fraction dose of 16 Gy or 18 Gy seems optimal for both pain palliation and local control. The patient should not expect this D3alliative treatment to increase survival.

Spine metastases

Spinal metastases may respond to radiation differently from other bone metastases. Ryu et al. reported the results of the NRG Oncology/RTOG 0631 randomized clinical trial. They tried to obtain proof that SBRT (16-18 Gy in one dose) was superior to IMRT in one dose (8 Gy) in terms of pain response. After 3 months, 61% of those treated with IMRT had a significant pain improvement vs 41% of those treated with SBRT. After 1 year, there was no difference in pain scores. After 2 years, there was no difference in spinal fractures or compression. 

There is conflicting data from other institutions. Sprave et al. at Heidelberg reported better pain response at 6 months (but not at 3 months) with SBRT (24 Gy in 1 fraction) vs 3DCRT (30 Gy in 10 fractions). Sahgal et al. in a Canadian/Australian multi-institutional trial, found there was a better pain response with SBRT (24 Gy in 2 fractions) compared to IMRT (20 Gy in 5 fractions). After 3 months, significant pain improvement was 35% for SBRT vs 14% for IMRT.

note: thanks to Valerae Lewis for allowing me to review the full text