Monday, August 29, 2016

SBRT for Oligometastatic Recurrence

Although the theory of the existence of a temporarily stable oligometastatic stage in prostate cancer is more than 20 years old, it remains unknown whether there is any benefit to pursuing curative or progression-delaying radiation if there are only a few metastases detected at recurrence. All of the studies so far have been very small, single-institution studies, lacking randomization, control groups, or consistent treatments. Ost et al. have pooled much of the existing data into a meta-analysis focusing only on those patients whose few metastases at recurrence were treated with SBRT.

In all, they identified 119 patients from 6 studies with the following characteristics:
  • ·      3 or fewer metastases were identified at recurrence any time after radical treatment.
o   One in 72%, two in 19%, three in 9%
o   163 metastases detected
o   Median time from diagnosis to detection: 4.7 years
  • ·      Primary metastasis sites were nodal (60%), bone (36%), or visceral (4%).
  • ·      Detection was via Choline PET/CT (77%), FDG PET/CT (20%), and MRI (3%).
  • ·      Median PSA at detection was 4.0 ng/ml, with a doubling time of 5.6 mos.
  • ·      Adjuvant ADT was used in half the cases for a median of 2 months (range: 1-8 mo.)
o   Excluded if ADT>12 months or ongoing at time of metastasis detection.
  • ·      Primary therapy was RP only (18%), RT (25%), or RP+aRT/sRT (57%).
After a median follow up of 3 years after SBRT treatment of metastases:
  • ·      Distant progression was detected in 61%.
o   Distant progression-free survival was 31% at 3 years, 15% at 5 years.
o   Median distant progression-free survival was 21 months.
o   70% had 3 or fewer metastases at time of progression.
  • ·      Median time to start of palliative ADT was 28 months.
o   Half received a second course of SBRT.
  • ·      Local progression-free survival was 93% at 3 years; 92% at 5 years.
o   Local progression was significantly greater at lower SBRT doses.
o   Local progression occurred at 18 months without adjuvant ADT, 25 months with adjuvant ADT, but the difference wasn’t statistically significant.
  • ·      Overall survival was 95% at 3 years, 88% at 5 years.
  • ·      Late Grade 2 GI toxicity was 3%, none greater.
The metastasis-directed SBRT treatment did an excellent job at eradicating the specific metastases at which it was directed, and the toxicity was remarkably low. However, that did not halt the cancer’s progression, except in 15% at 5 years, and presumably in fewer after longer follow up. The question remains, however, did the treatment slow down the cancer, allowing for many extra months and perhaps years of survival, and especially of symptom-free survival? After all, we were happy to get even a few months of extra survival out of our newest drugs like Xtandi, Zytiga, and Jevtana. There was no distant progression in these closely watched patients for almost 2 years, and even then, the metastatic burden was low. Given that there was almost no toxicity risk, should routine SBRT treatment of oligometastases at recurrence be a new standard of care?

That’s a very hard question to answer, even with the pooled data in this study. The problem is that we don’t know what would have happened had they not been treated. Were these patients really slow to progress, or do they only appear to be because they were so closely watched with advanced imaging from a very early point (lead-time bias)?

Some have theorized that there is a type of slowly metastasizing prostate cancer that these studies are selecting for – in that case, it is just a characteristic of that particular type of low-metastases prostate cancer and not the treatment that is slowing progression. We have seen so far in the CHAARTED trial that low-burden metastatic disease progresses and responds differently to docetaxel and ADT compared to polymetastatic prostate cancer. One study found that there is a microRNA that may distinguish between the oligometastatic type and the polymetastatic type. This hints at a distinct phenotype that may be particularly amenable to oligometastatic treatment. If so, perhaps we will eventually be able to identify biomarkers to select candidates for it.

On the other hand, a recent study that found that cancer often spreads from metastasis to metastasis bolsters the claim that oligometastatic treatment may be at least partially effective in all cases. To determine which hypothesis is true we’ll need clinical trials. Almost all of the studies on SBRT for oligometastases are very small, and have taken place in Europe. I am not aware of any planned clinical trial in the US. There are only a few Phase 2 trials in Spain, Germany, and Canada.

Because most of the detected oligometastases were in the pelvic lymph nodes, there is a special opportunity for lymph node-only treatment. Arguably, the entire pelvic lymph node area, and not just individual detected nodes, ought to be treated, and this was done in about 40% of the cases. There may be micrometastases that are too small to be detected in the pelvic lymph system. That area is typically not treated during primary radiation therapy, or during adjuvant/salvage radiation treatment. It may, in some cases be amenable to additional radiation if previous treatment was not too wide, was long ago, and anatomic considerations (e.g., visceral fat) allow for it. Recent analyses by Rusthoven et al. and by Abdollah et al. found a survival benefit to such whole pelvic salvage radiation (type unspecified), but Kaplan et al. failed to find a benefit. Salvage SBRT whole pelvic treatment for recurrent patients with positive nodes has yet to be explored in sufficient numbers of patients to draw conclusions about it.

With the growing number of test sites for the new generation of high-accuracy PET scans (e.g., C-11 Choline, Ga-68-PSMA, PET/MRI, etc.), it may become increasingly possible to detect advanced prostate cancer in the oligometastatic stage. SBRT treatment centers are also increasingly available, and the treatments are brief (typically 1-3 fractions), relatively inexpensive, and apparently very safe. As long as patient expectations are reasonable – that treatment may be able to delay, but not cure - it’s hard to argue against its use.

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