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 (or indeed other forms of targeted treatment) 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 six studies with the following characteristics:

  • Three or fewer metastases were identified at recurrence any time after radical treatment.
    • One in 72 percent, two in 19 percent, three in 9 percent
    • 163 metastases detected
    • Median time from diagnosis to detection: 4.7 years
  • Primary metastasis sites were nodal (60 percent), bone (36 percent), or visceral (4 percent).
  • Detection was via [11C]choline PET/CT (77 percent), FDG PET/CT (20 percent), and MRI (3 percent).
  • 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 to 8 months)
    • Excluded if ADT was given for more than 12 months or ongoing at time of detection of metastasis.
  • Primary therapy was radical prostatectomy (RP) only in 18 percent), radiation therapy (RT) in 25 percent, or RP + aRT/sRT  in 57 percent.

After a median follow -of 3 years after SBRT treatment of metastases:

  • Distant progression was detected in 61 percent.
    • Distant progression-free survival was
      • 31 percent at 3 years
      • 15 percent at 5 years
    • Median distant progression-free survival was 21 months.
    • 70 percent had three or fewer metastases at time of progression.
  • Median time to start of palliative ADT was 28 months.
    • Half received a second course of SBRT.
  • Local progression-free survival was
    • 93 percent at 3 years
    • 92 percent at 5 years
  • Local progression
    • Was significantly greater at lower doses of SBRT
    • Occurred at 18 months without adjuvant ADT and at 25 months with adjuvant ADT, but the difference wasn’t statistically significant.
  • Overall survival was
    • 95 percent at 3 years
    • 88 percent at 5 years
  • Late Grade 2 gastrointestinal toxicity was 3 percent, with none of higher grade.

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 percent 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 II 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 percent 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 whole pelvic SBRT 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., [11C]choline, 68Ga-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 one to three 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.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.

24 Responses

  1. Thanks Allen for reporting this interesting study with your helpful comments.

    I have two friends who have had spot radiation (neither had CyberKnife) for oligometastatic prostate cancer, both under the case management of Dr. Charles Myers, the well-known medical oncologist. For one of them who had several metastases, the treatment was delivered over a period of at least a month, done in Florida. He then had a recurrence at a single spot in bone, and that was treated by a one-time dose delivered locally. He is doing fine at about a couple of years since that treatment, and I find it encouraging that his recurrence was only a single spot that could be treated by a single dose that was delivered in his local area.

    The other patient also had a recurrence, with just a few metastases in different locations from the original metastatic sites, and he was retreated. I’m not sure of the details of his present situation but he seemed to be doing well.

    While these are just a couple of anecdotes, they lead me to think that even under expert management more than one treatment of oligometastatic disease may be needed. It makes sense that removal of these metastases eliminates the chance that the cancer in them could mutate to a more aggressive, explosive polymetastatic form of the disease, but, as you observe, that remains to be proven by research.

  2. With minimal number of bone mets, spot radiation can help with pain as well. But one should weigh this against the risk of fracture from too much radiation.

  3. I guess this finding is a bit disturbing.

    I’m embarking on a second round of ADT and IMRT — this time to all pelvic lymph nodes at Dattoli after rising PSA to 1.22 after failed RP, and SRT to the prostate bed only. No metastases were found in the prostate bed or bones so I guess RP and SRT were in fact “effective” but the horse had left the barn as my Gleason 9 was a fast-running steed.

    A recent MRI found that bilateral external iliac and common iliac lymph nodes are considered moderately to highly suspicious for lymphatic dissemination of my prostate carcinoma by morphologic MR criteria.

    Notwithstanding the conclusion of the aforementioned report, my hope is to stop the prostate cancer from moving beyond the few pelvic lymph nodes apparently involved and obtain a “durable remission”.

  4. Hi Bob and all who are interested in treating oligometastatic prostate cancer with spot radiation. I understand your concern, as I thought I would be following this path myself, and it would have been more reassuring if only a small proportion of patients in the study had a further recurrence after the first treatment of the oligometastatic (meaning few) metastases that had been detected. But here’s an analogy that seems applicable from my own experience with lawn care.

    I try to avoid broadcast weed killer as it is rough on the grass as well as the weeds, an objective which is analogous to trying to kill cancer while not permanently harming healthy cells. But this year the weeds got out of hand, and I had to use broadcast weed killer. As expected, that got rid of the vast majority of the weeds, though it was rough enough on the grass that I am now replanting a number of areas.

    However, some weeds remained, kind of like the small number of metastases (oligometastic disease) that can develop after regular first-line surgery or radiation, which, like the broadcast weed killer, knocks out the bulk of disease if not all. There are few enough weeds remaining that I am now giving them spot treatment, mainly by digging them up by the roots, which definitely eliminates those weeds, kind of like the first round of spot radiation treatment eliminating the detected metastases.

    I don’t expect that I got all the weeds, as some were likely too small to see, which is similar to micrometastatic disease that is too small for our excellent modern scans to detect. In the past, I’ve found there are very few of these stealthy weeds that survive the first round of spot treatment, but a second round of spot treatment virtually clears up the lawn. That second follow-up is likely to eliminate the spots that are expanding fast enough to be a concern. Metastatic spots — like any remaining very tiny and weakened weeds — that are tiny and also slow growing or dormant are perhaps of minimal threat. My hunch is that oligometastatic prostate cancer will often be treated the same way, with one or more follow-up spot treatments as needed, and that such treatment will give us many more years of good quality life.

  5. Jim,

    Repeated treatments were often used, and the doctors sort of played whack-a-mole with new metachronous metastases. Even so, progression-free survival continued to diminish over time. We haven’t seen very long follow-up in studies so far, but there seem to be very few who have lasting progression-free survival from this approach.

  6. I believe that Dr Snuffy Meyers is an example of lasting durable remission, no? Others who have attended Dattoli Cancer Center have testified to having their lives saved.

  7. Durable remissions among men with high-risk disease after first- and second-line treatment are not uncommon. They occur in men treated at all sorts of different clinical centers.

  8. When we hear testimonials, especially from people we know, it really sticks with us, doesn’t it? And if that gives us additional hope, it’s fine with me. However, it’s no substitute for data collected from large numbers of people, each of whom would have an anecdote of his own to tell. I think it’s a good idea to stay optimistic, but also to have reasonable expectations.

  9. As I like to encourage clinical trials and patient participation in them, I should have also mentioned one at Ghent University Hospital in Belgium. This is a randomized trial to see whether there is any delay in time to progression due to treatment with SBRT or PLND compared to just monitoring disease progression in men with three or fewer metastases detected at recurrence.

  10. Types of Radiation for Oligometastatic Disease, and Question for Bob

    Bob, will the Dattoli team be delivering IMRT to the whole pelvic area (as well as spot radiation where needed)? There is at least one important study indicating that early metastatic spread typically does not extend beyond the range of pelvic radiation. The leaders of the study don’t come to mind, but Dr. Myers has discussed it many times.

    My impression is that CyberKnife or any other radiation that can be aimed precisely, including IMRT, would be fine for detected metastatic spots. However, for micrometastatic disease that is suspected but not detectable because it is too small, wouldn’t a more broadcast type of radiation than CyberKnife be appropriate? IMRT is obviously good in that role, as it can dispense its dose in a shotgun pattern or rifle hit as needed.

  11. Dear Jim:

    There is a “chicken and egg” aspect to your question that is unanswerable.

    Any patient who has metastatic disease is always at risk for further micrometastatic disease (although exactly where that risk lies may become more predictable over time). The problem is that it is impossible to tell whether they have actual micrometastatic disease or not because even the most sophisticated imaging tests available today can’t identify truly micrometatstic tumors consisting, potentially, of only a very few cells.

    Similarly, any patient who is suspected of having micrometastatic disease might have a single tumor or multiple tumors — all too small to be accurately visualized.

    The question that Dr. Dattoli’s team might be better able to answer for Bob is not so much whether he is to get IMRT to the entire pelvis as well as the spot radiation but rather why he would or would not be well advised to do so in their opinion, based on his particular disease characteristics.

  12. Regarding the past several responses, in my own case, with challenging initial presentation back in late 1999 and doubling times during vacation periods from hormonal therapy of about 3 to 4 months (based on the period from a PSA of 5 to a PSA of 10), my radiation oncologist team deemed it best to do pelvic radiation despite not finding any metastatic sites with feraheme Ultrasmall Superparamagnetic Iron Oxide (USPIO) contrast agent MRI/CT (or in bone with the Na18F PET/CT bone scan). I certainly considered the option of not doing whole pelvis treatment, but joined my doctors in thinking, based mainly on the challenging aspects of my case initially and over the years, that the more aggressive approach was wiser to catch any micromets. It definitely crossed my mind that any such mets might not exist as they had had months to grow and appear evident, yet had not grown to the point of detection.

    As noted earlier, sensitive scans can identify fairly small metastases. After eliminating these, allowing time for others that are fairly aggressive, if any, to grow to the point where they should be detectable, should smoke out most or all of the rest that are aggressive, so they too can be eliminated with follow-up treatment. Thus the treatment strategy would be: initial treatment; recurrence; scan and treat any local recurrence and oligometastatic spots; allow time for growth of any remaining spots that were initially too small to detect; scan again; treat any remaining oligometastatic spots; allow time; scan again, hopefully with negative results.

  13. Jim,

    In contrast to the model you are using to think about this, the study above demonstrates that it is not the case, at least not in most cases. What they found is that local control is often excellent, especially with repeated treatments; however, distant mets almost always occurred eventually. Perhaps, if you need an analogy, mold spores might be a better one. They exist in the soil permanently and sprout up anywhere when conditions are right, even many years later. No matter how many times you pick mushrooms, they always grow back.

    SBRT can be used with any given treatment margin, just as IMRT can — in fact, many of the same machines are used to deliver both. The reason to limit the treatment margins — in either case – is to avoid toxicity. Whichever one decides to go with, fast machines and ones with good image tracking are likely to be less toxic. The German clinical trial cited above that compares SBRT and IMRT is designed with toxicity as the primary endpoint.

    As the local control was excellent with sufficient dose, 100% in fact, there is no oncological reason to switch to IMRT. In the studies used for the meta-analysis, the most utilized SBRT dose schedule was three treatments at 10 Gy each, and there was a strong relation between dose and local control. IMRT is typically given at 25 treatments at 2 Gy each, which is probably dose-limiting for that area. The biologically effective dose (BED) for killing the cancer is twice as high with the SBRT schedule, while they are exactly equivalent in the BED that causes acute toxicity in healthy tissue. IMRT may have an advantage in long-term effects, but so far, at least, long-term effects seem to be very small.

  14. I realize that Xofigo is for hormone non-sensitive and for only bone metastasis, but I wonder if it might be more effective to use earlier vs. radiating spots as they show up on scan. Does Xofigo go after even the micrometastases not seen on scans?

  15. Jerry:

    The only way that I can think of to answer the question you are raising accurately would be to carry out a large, randomized clinical trial among men with high-risk, ADT-sensitive disease suspected of having micrometastasis and measure time to evidence of actual, visible metastasis on a bone scan as a primary endpoint and overall and prostate cancer-specific survival as secondary endpoints. This might need to be a three-arm trial in which men would be randomized to one of the following forms of treatment after initial treatment with radiation therapy:

    (a) An extended period of ADT (probably at least 18 months and maybe 3 years since that has been proven to extend survival in such patients) + a placebo to substitute for treatment with the Xofigo
    (b) The same extended period of ADT + treatment with Xofigo
    (c) Treatment with Xofigo + a placebo to substitute for treatment with ADT

    Based on historical information, it seems likely that such patients would then need to be followed for some 5 years or more before one would be able to tell whether any one of the three treatments was any more effective than the other two (based on the primary endpoint), and one might need something like 750 patients to make the trial large enough to show a statistically significant result.

    There are questions about whether not giving such patients ADT (i.e., arm (c)) would be ethical, but without arm (c) it would be very hard to know whether real effects were being so significantly affected by treatment with ADT as to be near to meaningless. I am sure there are also other issues that would need careful consideration.

    It is already possible to give Xofigo to men with ADT-sensitive, metastatic prostate cancer, so it might also be possible to do a smaller, pilot study in men identified as having metastasis that shows up in bone on scans like the [11C]choline PET/CT scan but does not show up on a standard bone scan, but it would probably be extraordinarily difficult to enroll enough such men and to randomize them into a large Phase III trial.

  16. So if I have three iliac nodes suspicious for prostate cancer are those three nodes treated differently than the rest of the pelvic nodes? What would typical number of sessions be and total grays?

  17. Bob,

    As I mentioned in the article, it makes sense to me to treat the entire area, especially if there are as many as three positive nodes. While some ROs may boost the dose to the detected nodes, others would argue that it’s highly likely there are undetected mets throughout, and a curative dose is required everywhere. For SBRT, three fractions of 10 Gy each has been the most prevalent in the studies above. For IMRT, a typical dose schedule is 25 fractions at 2 Gy each.

  18. Allen et al.:

    I just found out that I’m scheduled for 50 sessions of DART to all nodes in the pelvic region with the same dose to all nodes. Only two iliac nodes were actually suspicious for prostate cancer but with Gleason 9 any one of them could have micromets. No organs, bones or distant nodes were found to have prostate cancer. All in all I’m thinking it’s not a bad report. I’ll also be on ADT (Lupron, Casodex, Avodart) plus cabergoline, sucralfate, pentoxifylline, an estradiol patch, vitamin D3, calcium, and metformin.

  19. Bob:

    50 sessions? That’s really unheard of. What’s the total radiation dose?

  20. Allen:

    I’ll find out Tuesday when I talk to dosimetrist. They have an out of the box approach here but I’m guessing they have lower doses per session but more sessions. Pelvic lymph node region is larger than prostate bed so maybe more total grays are required. Just guessing.

  21. I had IMRT (DART) to treat all pelvic nodes after MRI found suspicious iliac nodes after failed SRT. We have talked about how unusual you thought it was to get 50 sessions at 1.5 gray for 75 grays total.

    Given that you are not sure there is any overall survival benefit but you agree that RT possibly extends life in this setting so why not do it, what’s your view of using IMRT vs SBRT in terms of efficacy?

  22. So far, there is no evidence that either IMRT or SBRT for lymph node treatment is better in terms of cancer control or toxicity. If they are equal, the preference for the patient would be for the shorter, less expensive treatment, which would be SBRT. In general, grays are lower when a wider area is treated in which the cancer is more dispersed. (Remember that a gray is a measure of radiation absorbed per kilogram of tissue.) Thus, with conventional IMRT (2 Gy per treatment), about 80 Gy are used for the prostate alone, about 70 Gy are used for the prostate bed salvage, and about 50 Gy are used for the pelvic lymph node area. There is a risk for late-term toxicity to the small bowel. Careful imaging and planning are of paramount importance, and anatomical variances can make a big difference.

  23. Generally inadequate adjuvant ADT in initial radiation (prior to SBRT) for these patients (a tangent from the main theme on SBRT and oligometastasis)

    I have reviewed this thought-provoking article and the Ost paper (I read it all) prior to adding comments to Allen’s recent, similar article.

    Ongoing developments and research and a review of the article and study help highlight some key aspects of the Ost meta study.

    One key fact set is that there were many intermediate- and high-risk patients in this study (about 68%), 25% had radiation as a primary therapy, and 57% more had radiation subsequent to prostatectomy, bringing the total who had radiation as primary or secondary therapy to 82%. Yet the duration of ADT given was far below current practice: instead of around 4 to 6 months for intermediate cases and around 2 to 3 years for high-risk cases, the median duration of adjuvant ADT was only 2 months, and the maximum was 8 months.

  24. ADT was not much used to support treatment of these oligometastatic patients

    Review of the Ost study also revealed the limited use of ADT to try to eliminate oligometastatic disease in these studied patients.

    The significance here is that it seems likely that men treated today for oligometastatic disease would likely be on adjuvant ADT; I suspect their results would be substantially superior to the results in the Ost study. In essence, most men on ADT at the time of detection of metastases were excluded from the Ost study.

    My impression is that ADT would play a prominent support role these days. (That said, some of the sub-studies in this meta-analysis were exploring whether SBRT could help patients avoid or limit ADT in order to avoid ADT side effects.) My conclusion is that relief from distant metastasis in the meta study results, while meaningful, was not very long, and I suspect that ADT would have produced better results.

    Key facts from the meta study evidencing the limited use of ADT are that patients were excluded if:

    — “they had serum testosterone levels < 50 ng/ml at the time of detection of metastases; this would rule out most men on ADT because properly administered ADT for the vast majority of patients who do not clear the drug unusually rapidly will lower testosterone at least below < 50, and typically 12 mo at the time of SBRT;” this would rule out more men on ADT;

    — “had a biochemical relapse while on active treatment with ADT (including luteinising hormone-releasing hormone [LHRH] agonists, LHRH antagonists, antiandrogens, maximal androgen blockade, or oestrogens)”; this likely would cover those for whom ADT was not working well at all as the < 50 ng/ml men were covered above. This situation sometimes involves problems in delivering the drug or unusually rapid clearance of the drug.

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