Most of the recurrences after primary radiation failure are salvageable

Salvage therapy is curative in about half of men who have a biochemical failure after primary therapy. That's true whether the primary therapy was surgery or radiation. It's true when the salvage therapy was radiation after surgery. And it's true whether the salvage therapy was surgery, cryotherapy, or brachytherapy after radiation. Salvage success rates can be as high as 3 in 4, in certain well-selected patients treated with appropriate therapies (see this link, for example), but it can be a lot lower too. Salvage therapy always increases the complications over what they were for the primary therapy, so we would avoid it if we knew it was likely to be futile. Thanks to the new generation of PET scans, we are beginning to understand why, and what we may be able to do to improve those odds.

For any salvage therapy to be effective, two conditions must be met:

1.  The recurrence must be local. Local means in the prostate, seminal vesicles, the prostate bed, nearby organs (e.g., bladder, rectum, etc.), and/or in the pelvic lymph nodes.
2.  The recurrence must not be distant. Distant means metastases in the bones; remote organs like the lungs, liver, or remote lymph nodes; or in systemic circulation in the bloodstream.

In the past, it has been difficult to ascertain that both conditions were met. Bone scans are not very reliable when the PSA is below 20 ng/ml, and they are not specific for metastases. Moreover, by the time the PSA increases that much, the cancer is almost certainly distant and incurable. The NaF18 PET/CT scan can detect metastases sometimes at a PSA as low as 4 ng/ml, but it only detects bone metastases, and it is not specific for metastases. An Ultra-Small Superparamagnetic Iron Oxide (USPIO) MRI may sometimes detect metastases, but only in lymph nodes.  A multiparametric MRI may sometimes detect local recurrences, and may be used to target areas for biopsy in the prostate and prostate bed. It may be reliable after primary radiation (see this link). However, it tells us nothing about distant metastases.  CT scans only detect the larger lesions that may be suspect. A transperineal template mapping biopsy may detect prostate cancer in the prostate, but tells us nothing about distant metastases. It should be noted that biopsied prostate tissue looks very different after radiation, and it should be analyzed by highly experienced pathologists.

Clinical trials have proved that adjuvant radiation after prostatectomy has better outcomes than waiting, and recent studies suggest that overtreatment may be avoided by using early salvage radiation rather than adjuvant radiation therapy. Perhaps early salvage therapy after primary radiation therapy may have improved outcomes too. That is, it may be more successful if started before the patient's PSA reaches the nadir+2 level, which is the official definition of biochemical recurrence after primary radiation therapy.

The FDA-approved C-11 Choline PET/CT (or the similar C-11 Acetate PET/CT) fills some of the critical information gaps. It can detect prostate cancer in the radiation-treated prostate, the local area, and throughout the entire body at a PSA as low as 2 ng/ml, especially if the PSA has been rapidly rising. However, its sensitivity is not very good for small sites of cancer (they must be larger than 5mm), or cancer in lymph nodes. And when used to detect cancer within the prostate, prostatitis and BPH may generate false positives. Some of the new experimental PET scans (e.g., DCFPyL) may be more sensitive. Now that we have an adequate tool for detecting both of the above-mentioned conditions (local and not distant), we are beginning to be able to select which recurrences can be cured with salvage therapy, and which can only be managed with lifelong hormone therapy.

Parker et al. report on the Mayo Clinic experience with 184 patients with rising PSAs after primary radiation therapy on whom the C-11 Choline PET/CT was used to detect local and/or distant prostate cancer progression.

• 87% of patients were PET-positive.
• The C-11 Choline PET/CT correctly identified 98% of patients who were later found to have residual prostate cancer on subsequent histological analysis. 
• However, 42% of patients that were identified as negative by the C-11 Choline PET scan later suffered from cancer progression - they were false negatives.
• Patients were especially likely to be PET-positive if they had higher pretreatment PSA, were high risk, had higher PSA level at the time of the PET scan, had a greater increase from nadir PSA, had a shorter PSA doubling time, and had a higher PSA velocity. All of those with PSA≥ 10 ng/ml were PET-positive.
• Risk category, PSA increase from nadir, and time since primary radiation therapy were independently associated with PET-positivity, and can help predict when recurrences are salvageable.
• 59% of PET-positive patients were confirmed by histological analysis (either biopsy or salvage prostatectomy). 76% were confirmed by a multiparametric MRI.
• 46% of those who were PET-positive had cancer only in the prostate and seminal vesicles. These patients were potentially salvageable with any of the salvage therapies mentioned above.
• An additional 16% (62% in total) had cancer in the soft tissue pelvic region. These may be salvageable with extended pelvic lymph node dissection (ePLND) or radiation in select areas of the pelvis that were not treated originally.
• While only a few patients (21) had a PET scan before their PSA reached nadir+2, half of them had a local recurrence only, and are potentially salvageable. This suggests that the  patient does not have to wait for nadir+2. However on this small sample, the salvageability does not seem to be very different for those who detect it earlier.

This study confirms the findings of the larger study at Memorial Sloan Kettering (MSKCC) (reviewed at this link).  In that study, 55% had a recurrence in the prostate and/or seminal vesicles only, compared to 46% at Mayo. At MSKCC, an additional 8% had recurrences in the pelvic lymph nodes only, compared to 16% at Mayo. There were important differences between the studies. At Mayo, unlike MSKCC, patients may have had brachytherapy as all or part of their primary therapy, they may have had enlarged lymph nodes from the start, they had significantly lower doses of radiation (76 Gy vs ~80 Gy), they were younger (65 vs 69), fewer had adjuvant hormone therapy (30% vs 54%), they all had rising PSA but not necessarily nadir+2, and they all received a C-11 Choline PET/CT, there was less histological confirmation (59% vs 71%), and the median follow-up time was shorter (68 months vs 83 months).

As noted in the commentary of the MSKCC study, these findings may not apply when the primary therapy used a very high biologically effective radiation dose, such as with brachy boost therapy, SBRT, or high dose rate brachytherapy.

It makes sense to rule out the possibility of distant metastases using an advanced PET scan. Even at a cost of $2,500 or so, it may save the patient much more than that for the cost of salvage therapy. However, unless the PET scan is done at Mayo using C-11 Choline, is done as part of the clinical trial using the newly FDA-approved PET indicator fluciclovine, or is one of the free ones at NIH, the out-of-pocket cost may be formidable. Hopefully, the FDA will approve more of them, and availability will expand. Unfortunately for those considering early salvage after a prostatectomy failure, none of them are accurate for PSAs that low (≤0.2 ng/ml).

The authors constructed a nomogram to help the prospective patient predict whether his recurrence, detected with a C-11 Choline PET/CT, is likely to be a salvageable recurrence or unsalvageable recurrence. In the first table, fill in the number of points that comes closest to your situation, and add them up. In the second table, look up the probability of a distant recurrence (unsalvageable) that comes closest to your total number of points.

Risk Factor	Points to assign	My Points
PSA increase from nadir	2 ng/ml: 13 5 ng/ml: 32 10 ng/ml: 63 15 ng/ml: 95
Years since RT	1 yr: 100 2 yrs: 95 3 yrs: 90 5 yrs: 80 10 yrs: 52 20 yrs: 0
Risk Group	Low: 0 Intermediate: 8 High: 45
	TOTAL

My Total Points	Probability of recurrence outside of the pelvic area
66	5%
88	10%
120	25%
153	50%
185	75%
216	90%
240	95%

This nomogram outperformed using a PSA threshold alone in its predictive power, and may help the patient decide whether potentially-curative salvage therapy or lifelong hormone therapy is the better course of action.

I'm not sure why radiation dose was not significantly correlated with the site of recurrence at Mayo (p = 0.1) as it was in the MSKCC study. In fact at MSKCC, those who received doses of at least 79.2 Gy had half the rate of recurrence compared to those who only received 75.6 Gy (which seemed to be the norm at Mayo). It may be that those who were treated at Mayo only received higher doses when their cancer was already systemic. We know that this is on the steep part of the dose/response curve where even a small increase in dose can increase its effectiveness greatly. Whatever the reason for the data discrepancy, higher doses do prevent local recurrences.

(update 11/18/2018) Hayman et al. reported on 49 men who had a biochemical recurrence after whole pelvic primary radiation therapy and long-term ADT who were clinically staged as node positive (N1) via MRI. Using imaging (probably a PET/CT scan) they found the site(s) of recurrence in 46 of the men:

• 25 (54%) had a recurrence in the prostate only
• None had a recurrence in lymph nodes only
• 21 (46%) had a recurrence that included a distant metastasis

This is very similar to Mayo and MSK.

note: Thanks to Dr. Will Parker for letting me review the full text of his published study.

Can Ga-68-PSMA PET/CT scan change radiation treatment decisions?

A diagnostic technique is valuable only insofar as it is able to change treatment decisions. A small Australian study claims that GA-68-PSMA PET/CT scans can in about half the cases.

Thomas Shakespeare diagnosed 54 patients using a Ga-68-PSMA PET/CT. He selected patients with any of the following characteristics:

• ·      Equivocal results on bone scan, CT or MRI
• ·      Negative bone scan, CT or MRI, but reason to question those findings
• ·      Suspected as having oligometastatic PC (1-3 nodal or distant metastases)
• ·      If post-primary treatment, PSA<10 and no detected metastases

The potential decisions to be made were whether to…

• ·      pursue curative primary IMRT in 15%.
• ·      pursue salvage IMRT in 33%.
• ·      pursue radiation of oligometastases after primary RT or salvage RT in 50%.
• ·      determine response to systemic therapy in 2%.

After PSMA-PET diagnosis, the treatment plans changed as follows:

• ·      Observation: 50%-> 19%
• ·      IMRT (primary or salvage): 33% -> 28%
• ·      Oligometastatic treatment: 9% -> 37%
• ·      Systemic therapy (ADT and/or chemo) only: 7% -> 17%

When conventional imaging was negative, PSMA-PET was also negative in 32% of cases, but was positive in 46% of cases. When conventional imaging gave equivocal results, PSMA-PET was split pretty evenly – negative in 7 cases (13%), positive in 5 (9%).

The PSMA-PET had little effect on the primary/salvage IMRT decision. Most of its effect was in detecting oligometastases for palliative treatment, and the remainder in detecting patients who were found to be poor candidates for any radiation therapy.

The radiation treatment of oligometastases continues to be controversial, with the most recent data showing little or no curative benefit. Although Dr. Shakespeare is careful to label the treatment of oligometastatic prostate cancer as “palliative,” he elsewhere writes: “In our study, potentially curable patients were found to be incurable, and potentially incurable patients were found to be curable.”  While it’s true that 5 extra patients (9%) were given systemic (non-curative) therapy only, there do not seem to be any who were discovered to be “potentially curable.” If Dr. Shakespeare were to follow US standard-of-care protocols (i.e., no non-palliative radiation treatment of oligometastases) and treat those with oligometastases with observation or systemic therapy only, there would have been little change in treatment decisions: 3 of the 18 patients (17%) originally planned for curative radiation would have been assigned to observation or systemic treatment.

There is no question that PSMA-PET scans are more accurate than conventional imaging, but it remains an open question as to whether that enhanced accuracy will change radiation therapy decisions as it is currently practiced in the US enough to justify the increased cost.