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.

Free Randomized Clinical Trial of Ga-68-PSMA-11 PET indicator at UCLA

UCLA is now running a randomized clinical trial of the Ga-68-PSMA-11 PET indicator for men  with a recurrence (PSA≥ 0.1 ng/ml) after prostatectomy who are considering salvage radiation therapy (SRT). They are expanding and adding a control arm to the trial they did earlier (see this link) that found that the PSMA-based PET scan was able to change treatment decisions in about half the men.

Here are the trial details and the contact info:
https://clinicaltrials.gov/ct2/show/NCT03582774

UCLA normally charges $2650 for the PET indicator, so this is an opportunity to save some money. If a patient is randomized to the control group, he may still get an Axumin PET scan when his PSA is confirmed above 0.2 ng/ml, which is covered by Medicare and most insurance. The Axumin PET scan only detects cancer in 38% of patients if their PSA is in the range of 0.2-1.0 ng/ml, while the Ga-68-PSMA-11 PET scan detects cancer in about 27%-58% of recurrent men whose PSA is between 0.2 and 0.5. UCLA recently completed another free clinical trial comparing Axumin to Ga-68-PSMA.

I'm told that the NIH trial of another PSMA PET indicator, DCFPyL, has a waiting list of 2-3 months, and they are no longer taking patients whose PSA is below 0.5 ng/ml. It is possible to pay for PSMA-based PET scans in Germany and Australia. The newest and perhaps most accurate PSMA-based PET indicator, F(18)-PSMA-1007, is in clinical trials in Germany (see this link).

This trial is not open to men who have already had SRT, have known metastases, have had ADT within the last 3 months, or who cannot have radiation for any reason.

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).

Use of mpMRI and PSMA PET/CT to aid in salvage radiation decision-making

Because the success or failure of salvage radiation (SRT) hinges upon whether micrometastases are already systemic at the time of treatment, evidence that the cancer is still local improves the odds that SRT will be successful.. One way of finding local tumors is to use multiparametric MRI (mpMRI). mpMRI can detect tumors down to about a limit of 4 mm, and may be able to find tumors even when their PSA output is low.

Sharma et al. at the Mayo Clinic retrospectively examined the records of 473 men who were treated with SRT and who had an mpMRI prior to treatment from 2003 to 2013. Among men with a pre-treatment PSA ≤ 0.5 ng/ml, 5-year biochemical failure was:

• 39% among those with a negative mpMRI
• 12% among those with a positive mpMRI

Adding mpMRI to the updated Stephenson nomogram (see this link) increased its predictive accuracy for PSA recurrence after SRT from 71% to 77%. Perhaps its accuracy would increase even further if the MRI was confirmed by a biopsy of the suspicious tissue to eliminate any false positives.

Like the detection of a positive margin in post-prostatectomy pathology, detection of a local tumor using mpMRI increases the probability that SRT will be successful. Although the radiation dose to the suspicious lesion can be boosted (see this link), it is unknown whether such a boost actually increases efficacy when the entire prostate bed is adequately treated. It is also unknown what effect it might have on toxicity. Moreover, it is hard to argue for a reduced dose elsewhere in the prostate bed because of the known limitation of mpMRI in detecting smaller tumors, and the multi-focal nature of prostate cancer spreading.


Emmett et al. at St. Vincent Hospital in Sydney performed a Ga-68-PSMA-11 PET/CT on 164 men with rising PSA (PSA range: 0.05-1.0 ng/ml) after prostatectomy who received SRT. After eliminating patients who also had systemic therapy, there were 140 evaluable patients. They had a pre-SRT PSA of 0.23 (interquartile range 0.14-0.35).  As expected, detection rates went up with increasing PSA;

• <0.2 ng/ml: 50%
• 0.20-0.29 ng/ml: 64%
• 0.30-0.39 ng/ml: 67%
• ≥0.40 ng/ml: 81% 

They only had 10.5 months of median follow-up, and defined a favorable PSA response to SRT as a decrease of at least 50% in PSA and a PSA ≤ 0.1 ng/ml (those receiving adjuvant ADT were eliminated from the follow-up PSA-response analysis). The results should be interpreted with caution because of the very short follow up and low sample sizes. A short-term PSA response only indicates local control, and may not endure if systemic micrometastases were present.

PET/CT was negative in 38% (62/164). 45% of those men (27/60) had SRT to the prostate bed, and 7/27 had SRT to the pelvic lymph nodes field too. In the "negative" detection group, 86% had a favorable PSA response to SRT. Unfortunately, more than half of the PET-negative men never received SRT. This should serve as a caution against over-reliance on PET/CT. PET/CT is not good at detecting micrometastases in the prostate bed. The prostate bed is also a difficult place to detect PSMA-avid cancer because of masking from urinary excretion. We also know little about the natural history of PSMA development in prostate cancer -- it  may very well be that earlier forms of the cancer that may not express PSMA may be most vulnerable to SRT. SRT should never be withheld from an area based solely on negative PSMA findings.

PET/CT was positive in the prostate bed only in 23% (38/164). All of them had SRT to the prostate bed, and 17/36 had SRT to the pelvic lymph node field too. In the "prostate-bed only" detection group, 81% had a favorable PSA response to SRT. Recent evidence indicates that pelvic lymph node SRT increases effectiveness (see this link). Radiation of the pelvic lymph nodes should be considered in spite of negative nodal PSMA findings.

PET/CT was positive in pelvic lymph nodes in 25% (41/164). 87% (26/30) of them had SRT to the prostate bed and to the targeted pelvic lymph nodes. In the "pelvic lymph node" detection group, 61.5% had a favorable PSA response to SRT. The entire pelvic lymph node field and not just isolated lymph nodes should receive SRT for the reasons stated above.

PET/CT was positive for distant metastases in 14% (23/164). Nevertheless, 60% (10/15) of them had SRT to the prostate bed (and, I suppose, to the entire pelvic lymph node field), and 6/10 had metastasis-directed SBRT too. In the "distant metastasis" detection group, only 30% had a favorable PSA response to SRT. Only 1 of the 6 who had metastasis-directed SBRT had a favorable PSA response. When there are known distant metastases, treatment of the prostate bed, pelvic lymph nodes, and of metastases remains a controversial treatment.

The PET/CT was a better predictor of SRT response than PSA, Gleason score, stage, or surgical margin status. The most valuable finding of this small, short-term analysis was that metastases can sometimes be detected at fairly low PSA (as low as 0.1 ng/ml), and it may be possible to rule out SRT in those cases. Conversely, when distant metastases cannot be detected, SRT success rates may be very good.

We will require longer follow-up, larger sample size, prospective studies to establish the utility of mpMRI and PSMA PET/CT in SRT decision making. The two imaging techniques are complementary - the MRI is not as PSA-dependent and is not masked by the urinary excretion of the radiotracer, while the PET scan is highly specific for cancer. Both are useless in detecting tumors with a dimension smaller than 4 mm, so it would be a mistake to think that what is detected is all there is.