Most recurrences after primary radiation failure are salvageable


Salvage therapy is curative in about half of the men who have a biochemical failure after primary therapy for localized prostate cancer. 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.

However, 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. Owing 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:

  • 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.
  • The recurrence mustnot be distant. Distant means metastases in the bones; in 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 Na18F PET/CT scan can sometimes detect metastases 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 also 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 over-treatment 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 ng/ml level, which is the official definition of biochemical recurrence after primary radiation therapy.

The FDA-approved [11C]choline PET/CT fills some of the critical information gaps (as does the similar [11C]acetate PET/CT scan). 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 5 mm), 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. have just reported on the Mayo Clinic experience with 184 patients with rising PSAs after primary radiation therapy on whom the [11C]choline PET/CT scan was used to detect local and/or distant prostate cancer progression.

  • 87 percent of patients were PET/CT-positive.
  • The [11C]choline PET/CT scan correctly identified 98 percent of patients who were later found to have residual prostate cancer on subsequent histological analysis.
  • However, 42 percent of patients that were identified as negative by the [11C]choline PET/CT scan later suffered from cancer progression — i.e., they were false negatives.
  • Patients were especially likely to be PET/CT-positive if they had higher pretreatment PSA levels, were high risk, had a higher PSA level at the time of the PET/CT 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 levels ≥ 10 ng/ml were PET/CT-positive.
  • Risk category, PSA increase from nadir, and time since primary radiation therapy were independently associated with PET/CT-positivity, and can help predict when recurrences are salvageable.
  • 59 percent of PET/CT-positive patients were confirmed by histological analysis (either biopsy or salvage prostatectomy). 76% were confirmed by a multiparametric MRI.
  • 46 percent of those who were PET/CT-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 percent (62 percent in total) had cancer in the soft tissue pelvic region. These may be salvageable with extended pelvic lymph node dissection (ePLND) or radiation to select areas of the pelvis that were not treated originally.
  • While only a few patients (n = 21) had a PET/CT scan before their PSA reached nadir + 2 ng/ml, half of them had a local recurrence only, and so were potentially salvageable. This suggests that the patient does not have to wait for nadir + 2 ng/ml. However, based 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 Cancer Center (MSKCC) (reviewed at this link). In that study, 55 percent had a recurrence in the prostate and/or seminal vesicles only, compared to 46 percent at the Mayo Clinic. At MSKCC, an additional 8 percent had recurrences in the pelvic lymph nodes only, compared to 16 percent at the Mayo Clinic. There were important differences between the studies. At the Mayo Clinic, unlike at 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 on average (65 vs. 69 years); fewer had adjuvant hormone therapy (30 vs. 54 percent); they all had rising PSA levels — but not necessarily nadir + 2 ng/ml; they all received a [11C]choline PET/CT scan; there was less histological confirmation (59 vs. 71 percent); and the median follow-up time was shorter (68 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 the Mayo Clinic, using the [11C]choline PET/CT scan, is done as part of the clinical trial using the newly FDA-approved PET indicator fluciclovine, or is one of the free ones at the National Institutes of Health Clinical Center in Bethesda, the out-of-pocket cost may be formidable. Hopefully, the FDA will approve more of these types of scan in the near future, 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 [11C]choline PET/CT scan, is likely to be a salvageable recurrence or an unsalvageable recurrence. In the first table, one must fill in the number of points that comes closest to your situation, and add them up. In the second table, one must look up the probability of a distant recurrence (unsalvageable) that comes closest to your total number of points.

z1

z2

This nomogram outperformed the use of 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 for him as an individual.

I’m not sure why radiation dose was not significantly correlated with the site of recurrence at the Mayo Clinic (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 received only 75.6 Gy (which seemed to be the norm at the Mayo Clinic). It may be that those who were treated at the Mayo Clinic 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.

Editorial note: This commentary was written by Allen Edel, with thanks to Dr. William Parker of the Mayo Clinic for providing the full text of his published study for review. Also, please note that the two tables above have been revised from those originally posted on September 13, when there were critical errors in the upper table. We apologize for this error on our part.

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