Prostate Cancer News, Reviews & Views: Targeting Bone Metastases with Radiation in Oligorecurrent Men has No Survival Benefit in Mayo Study

Oligometastases in bones

Metastasis-directed therapy (MDT) when there are only a few bone metastases (called "oligometastatic") is controversial. It can certainly relieve pain, and prevent fractures and spinal compression. It can also provide good "local control" (cancer in the irradiated metastasis is permanently destroyed) and reduce the PSA that those metastases put out. But is there any survival benefit?

Patients often ask radiation oncologists (ROs) for radiation of those metastases using targeted radiation (which I'll call "zapping"), and they ask their ROs to treat new metastases as they are detected. This is called "metachronous treatment," but I'll call it "whack-a-mole" Sometimes metastases appear in places where radiation treatment may be problematic, such as near vital organs or deep in the spine. The nagging question is whether such treatment really does the patient any good. With the approval of ever more sensitive PET scans, like the PSMA PET scan approved last week, patients will undoubtedly detect more metastases.

The Mayo Clinic has been one of the cheerleaders for MDT. They have posted a deceptive youtube video featuring their C-11 Choline PET scans showing only how good the local control is. What the video can't show is how those patients would have done without MDT - there was no control group ever used or shown in their video.

Perhaps to partially correct for the misleading video, Boeri et al. at Mayo retrospectively looked at 115 patients who had an oligometastatic recurrence to the bones (1-5 metastases):

115 patients were treated with SBRT. They had a median of 1 bone metastasis.
47 patients were treated with ADT-only. They had a median of 2 bone metastases.

This was not a randomized study, so it is entirely likely that there was "selection bias" -- those who received ADT-only may be because it was felt they would not be able to benefit from SBRT or that it might be unsafe. Patients who received ADT-only had a higher number of bone metastases and a higher PSA. All of those receiving MDT for bone metastases were also receiving ADT.

The 5-year prostate cancer mortality was no different between the two groups
The 5-year radiographic recurrence-free survival was no different between the two groups
Among those with 5 years of follow-up, the time remaining free of the next significant systemic therapy (e.g., chemo, Zytiga, etc.) was longer for those getting zapped. However, it should be noted that the decision to give an additional significant therapy is a physician decision based on many factors, including patient status, number of metastases, and PSA. Because number of metastases and PSA are changed by MDT, and those receiving MDT started with one less metastasis, the physician may feel pressured to start a new therapy sooner in patients receiving ADT-only.

Pending confirmation from long-term randomized clinical trials of MDT to oligometastases in bones, there is no evidence of oncological benefit.

Oligometastases in Pelvic Lymph Nodes (PLNs)

MDT of oligorecurrent metastases that are only in pelvic lymph nodes (PLNs) is less controversial. Lymph is a slow-moving fluid, and metastatic cancer cells emerging from the prostate might get trapped in the lymph nodes that drain the prostate. So it has been hypothesized that treatment of the PLNs when a few are found to be cancerous may still provide a cure. This has not yet been proven in a randomized clinical trial, but there is observational evidence of a significant benefit to salvage whole-pelvic radiation (see this link).

What is controversial about the way they are treated at the Mayo Clinic is that only those cancerous PLNs and a small margin around them were surgically removed, and whole pelvic salvage radiation wasn't routinely given. They were treated in any of three ways:

Salvage Pelvic Lymph Node Dissection (sPLND). Jeffrey Karnes at Mayo is one of the few top surgeons in the US who does this difficult surgery. It is difficult because PLNs detected on a PET scan can be very small. They are invisible, can be hidden in fat deposits, and are very difficult to find. There are innovative techniques like fluorescent or gamma-ray PSMA indicators that can facilitate detection. Patients treated with sPLND also received 6 weeks of bicalutamide.
External Beam Radiotherapy (EBRT) to PLNs as part of salvage radiation treatment (SRT). At Mayo, 72% received salvage IMRT to the identified PLNs plus a large margin around them, while 28% received SBRT to just the identified PLNs plus a small margin around them. This was typically done along with 12-18 months of ADT.
ADT-only, Patients treated with either of these two forms of MDT were compared to patients who received ADT-only, which is the current standard-of-care. Again, this was not part of a randomized clinical trial, so it is likely that the ADT-only patients were not offered MDT for a reason. Most importantly, about half had cancerous LNs in the retroperitoneum or abdomen (Stage M1a) - already outside of the prostate drainage area (Stage N1), and they had more positive LNs. In contrast, only 9% of the sLND group and 19% of the EBRT group had cancerous LNs outside the pelvis. The ADT-only group had much further progression at the time of treatment.

After a median follow-up of 47 months:

Prostate Cancer-specific mortality was 13.5% for ADT-only, 9.5% for EBRT, and 6.3% for sLND (the difference between ADT-only and sLND was statistically significant)
Radiographic recurrence was 65% for ADT-only, 40% for EBRT, and 61% for sLND.
Castration-resistance was 39% for ADT-only, 19% for EBRT, and 21% for sLND.
- The median time until castration-resistance set in was 59 months for ADT-only, 73 months for EBRT, and 98 months for sLND.
Second-line systemic therapies were offered to 43% for ADT-only, 29% for EBRT, and 24% for sLND.
- The median time until the therapies were offered was 28 months for ADT-only, 32 months for EBRT, and 44 months for sLND.
Inexplicably, the percent of cancerous lymph nodes outside of the pelvis (% M1a) was not included as a variable to correct for in their multivariable analysis, and was largely ignored.

The authors found an association between MDT and radiographic progression in their retrospective sample of patients. However, it leaves unanalyzed how much of that association is due to the extraordinarily high rate of out-of-pelvis progression already present in the ADT-only treated patients. In fact, it seems likely that that is the reason they didn't receive MDT.

They also make the same error with respect to castration-resistance and use of second-line therapies that they made in their bone MDT analysis; i.e., they "treated PSA" with their MDT, so they can't use castration-resistance and time to second-line therapy as useful endpoints. Tellingly, radiographic recurrence is similar for ADT-only and sLND, while EBRT is lower, possibly only because of the longer use of adjuvant ADT with EBRT.

Another open question is whether whole pelvic salvage radiation might have been more effective than the limited margins they used at Mayo. With the more accurate PSMA PET scans, ROs are able to treat the entire PLN area with radiation boosts given to the detected ones. The RTOG-consensus treatment area has recently been expanded (see this link). It's important that patients understand the detection limits of even the best PSMA PET scan: metastases smaller than 4 mm, and those that put out only small amounts of PSA remain invisible.

(Update 12/30/2020) Farolfi et al. reported on 16 patients who received sLND based on PSMA PET scan detection, and still had persistently detectable PSA 6 weeks later. They were given a second PSMA PET scan. Additional cancerous PLNs were found in 56% (in an additional 31%, cancer was found in non-pelvic LNs). In 63% of patients, the PLN cancers were in at least one of the same sites. This shows how poor surgical dissection is for PLN metastases, even with PSMA PET guidance.

Other articles about studies of oligometastatic prostate cancer: