Recently we have seen evidence of improved cancer control in high-risk patients treated with external beam radiotherapy with a brachytherapy boost to the prostate. This has been demonstrated with both HDR brachytherapy boost and with LDR brachytherapy boost.
Can the same cancer control be obtained with intensity-modulated radiation therapy (IMRT) and a boost to the prostate delivered with stereotactic body radiation therapy (SBRT)?
Anwar et al. reported the outcomes of 48 intermediate and high-risk patients treated with SBRT boost therapy between 2006 and 2012 at the University of California San Francisco. Of these 48 patients, 34 (71 percent) were high risk, and 14 (29 percent) were intermediate risk.
The treatment consisted of:
- IMRT: 45 to 50 Gy in 25 fractions to the entire pelvis if the risk of lymph node involvement was > 15 percent, otherwise with a 1 cm margin.
- SBRT boost: 9.5 or 10.5 Gy in 2 fractions to the prostate, seminal vesicles + a 2 mm margin, 0 mm on the rectal side.
- Heterogeneous planning was used to mimic HDR brachytherapy dosimetry.
- Gold fiducials were used for daily (IMRT) and intra-fractional (SBRT) image tracking.
- Intermediate-risk patients had 4 to 6 months of adjuvant hormone therapy.
- High-risk patients had up to 2 years of adjuvant hormone therapy.
After a median of follow-up of 42.7 months, they reported the following results:
- 5-year biochemical no evidence of disease: 90 percent
- PSA nadir (median): 0.05 ng/ml
- 2 patients had a PSA bounce over 2 ng/ml, which declined with longer follow-up
- 4 patients had a clinical recurrence outside of the radiation field
- Local control (within the radiation field) was 100 percent.
- Acute toxicity:
- Urinary, grade 2: 17 percent
- Rectal, grade 2: 10 percent
- Late toxicity:
- Urinary, grade 2: 25 percent; grade 3: 1 patient
- Rectal, grade 2 or higher: none
Clearly, these are excellent results for cancer control. The table below shows outcomes in similar trials of SBRT boost treatments and of SBRT monotherapy:
Compared to these other small trials, Anwar et al. used significantly higher effective doses of radiation and got perhaps better control (remembering that almost a third were intermediate risk), but late-term urinary toxicity was high. Lin et al. used lower doses, had similar control in their all high-risk group trial at 3 years, and none suffered from late-term urinary toxicity. Katz and Kang treated consecutive high-risk patients with SBRT boost and with monotherapy, respectively, but had the same cancer control in both groups, and the late-term urinary toxicity was not significantly different. Katz and Kang concluded that the SBRT boost accomplished nothing compared to the monotherapy, and also found that ADT use did not contribute to cancer control in his patients. He treated all subsequent high-risk patients with SBRT monotherapy only and without ADT.
We can also look at the Anwar outcomes next to those of a recent LDR brachytherapy boost therapy trial (ASCENDE-RT) and an HDR monotherapy trial (Hoskin et al.) in the table below:
SBRT boost therapy seems to provide similar rates of cancer control, but with less late-term urinary toxicity compared to brachy boost therapy or HDR-BT monotherapy.
In an interesting twist, Memorial Sloan-Kettering Cancer Center is running a clinical trial of SBRT supplemented with an LDR-BT boost to the prostate in intermediate-risk men (NCT02280356). I would guess that this would have considerable toxicity, but the clinical trial will prove or disprove that hypothesis.
So far, trials of SBRT boost therapy are too small to draw anything but provisional conclusions. There is a larger trial nearing completion at Georgetown University Hospital next month. Based on these pilot studies, SBRT boost therapy seems to be capable of providing good cancer control in high-risk patients and may be able to accomplish that with less toxicity than brachytherapy-based treatments. As we’ve seen, SBRT monotherapy and HDR brachy monotherapy are emerging therapies for high-risk patients as well. It would certainly be a lot more convenient to accomplish the same cancer control, at lower cost, and with perhaps less toxicity using just 5 SBRT monotherapy treatments instead of 27 treatments with SBRT boost. Only a prospective, randomized, comparative clinical trial can tell us whether one therapy is better than another. The most appropriate radiation dose level, dose constraints, the size of margins, lymph node treatment, and whether adjuvant ADT provides any benefit are variables yet to be determined.
This is an area of active investigation. If readers are interested in participating in a clinical trial of SBRT boost therapy, below is a list of open trials and their locations:
- Fountain Valley, CA (NCT02016248)
- Sacramento, CA (NCT02064036)
- San Francisco, CA (NCT02546427)
- Miami, FL (NCT02307058)
- Park Ridge, IL (NCT01985828)
- Boston, MA (NCT01508390)
- Madison, WI (NCT02470897)
- Scottsdale, AZ (NCT02339948)
- Ft. Myers, FL (NCT02339948)
- Plantation, FL (NCT02339948)
- Farmington Hills, MI (NCT02339948)
- Myrtle Beach, SC (NCT02339948)
- Sydney, Australia (NCT02004223)
- Gliwice, Poland (NCT01839994)
- Poznan, Poland (NCT02300389)
Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: body, boost, radiation, stereotactic, therapy |
THE "NEW" PROSTATE CANCER INFOLINK 
Thanks Allen for this interesting review which documents substantial progress in treating high-risk (and intermediate) cases especially with SBRT.
The success rates for both Katz and Kang studies struck me as a bit inferior to what is being achieved these days as it seems that at least 80% success at 5 years for high-risk patients is becoming par for the course. Do you see it that way? I’m curious why the results are lower than in other studies.
Jim,
This is where these kinds of comparisons fall apart. The only true way of comparing is with a randomized trial. Otherwise, we run into questions about how progressed the patients were at the time of treatment, and how they were selected. Katz’s cancer control seems similar to the 7-year bRFS of 68% reported for the very high-dose IMRT (86 Gy, which is a similar BED to what Katz used) given to the high-risk patients at MSKCC (Katz’s toxicity is lower). So it may be dose related. Yet Katz reports no difference in cancer control (but a difference in toxicity) when he treated patients with a higher dose. King is using a higher dose (40 Gy), optionally treating pelvic lymph nodes, and optionally using up to 9 months of ADT in his SBRT monotherapy clinical trial, so we will have to await his results. For now, the standard of care for high-risk patients remains boost therapy.
Your Reply
I appreciate your reply and view, and I’m disappointed to learn of that relatively low success rate for the 86 Gy series at MSKCC.
As you know, I am convinced we need to use analysis as well as straightforward trial results, but I take your point that a well executed trial would be the best evidence.
Good to see these results. My treatment was close to the Anwar trial, except that I got neoadjuvant therapy for, I think, 6 months and adjuvant therapy for 3 years, not 2 years. And EBRT, not SBRT. The results roughly agree, except for a higher percentage recurrence free at 5 years. I am at roughly 6 years post-radiotherapy, with no detectable recurrence.
Toxicity agrees too, with grade 2 urinary toxicity and nothing else right now. I did have some sort of gastrointestinal problem, but that vanished. No idea what that was.
The urinary issue is radiation-induced cystitis, in the area where prostate, bladder, and urethra converge. I saw the inflammation and coagulated blood from an acute lesion, on the monitor during a cytoscopy. Interesting! A CT scan revealed no renal involvement. I take an alpha-blocker to manage the cystitis. It increases blood flow in prostate and bladder by relaxing muscles, I think. I did not tolerate anticholinergic tablets, which is standard for this type of cystitis.
Cystitis seems unavoidable, as that area was within the margin of the total irradiation, I think mainly of the HDR. I seem to remember being told that some of the 12 or so HDR catheters were placed so as to make that margin. I think the oncologist used a margin of 1 cm. The moral is, that if you want to irradiate the right prostate volume and do your best to kill any cancer surrounding that, then a margin is a way to do that. If so, then you irradiate the region I am talking about, and cause damage to healthy tissue, not only cancer cells. But I’m no doctor, so maybe I am just blabbing on.
Insight into ADT Use/Non-Use in the Katz and Kang Series
A free copy of the complete paper is fortunately available online, and I have begun to study it. I was puzzled why the authors saw no benefit to ADT in high-risk men and discontinued its use part-way into their series. There appears to be a simple and unfortunate answer: the duration of ADT was simply too short, almost certainly far too short.
Here is the authors’ interpretation of the lack of influence of ADT: “It should be noted that all of the above studies found no benefit to the use of short-term ADT, prior to or during radiotherapy. The evidence that ADT improves the outcomes with radiotherapy is with the use of low doses of 66–70 Gy …. This benefit seems to disappear with higher radiation doses, as we have found in our study. More trials to test this may be necessary.”
Here is a key statement from the complete paper about the use of ADT: “50 patients received hormone therapy for a median of 5 months (range, 1–13 months)”. That median of 5 months means that half of the 50 patients, 25 patients, received ADT that was only 5 or fewer months, and the range of 1 to 13 months means that no patient received ADT of 14 or more months. Patients in the series were treated between April 2006 and May 2011.
A widely reported clinical trial of ADT to support radiation a few years ago found that 2 years of ADT were superior to 6 months of ADT, for high-risk patients as I recall. Therefore, I believe the evidence is strong that the authors were using an inadequate duration of ADT, including a greatly inadequate duration for 25 of their patients, and that this alone is enough to explain the lack of influence of ADT.
I agree with Jim W. on the issue of ADT duration and lack of influence. In case it wasn’t clear from the above commentary, the title of the Katz-Kang paper, in part, reads: SBRT … in “organ confined” high-risk prostate carcinoma.
Here we go, Len and Jim. Click here.
Katz’s ADT treatment was bimodal: about half receiving it for a year, and about half receiving it for less than 3 months. He found no difference in biochemical recurrence-free survival with that level of ADT use. I don’t know if he ever looked at the shorter term vs. the longer term — that stretches the sample a bit thin.
Until we got the results of DART 01/05 last year, we had no high level evidence that long-term ADT was of any benefit when used with escalated doses of IMRT radiation in high-risk patients. In fact, the available evidence that Katz cites in his 2014 paper leaned in the other direction. This once again highlights the importance of randomized clinical trials.
Even with DART 01/05, one can’t look at IMRT results and assume they apply to SBRT as well. IMRT and SBRT are different in their radiobiological effects. Because cancer cell kill rates are so much more efficient with SBRT, it remains unclear that there is any advantage to adjuvant ADT with it. The lack of benefit of ADT with extreme hypofractionation was shown by Demanes in 2009. We certainly don’t want to give systemic hormone therapy for any length of time if there is no benefit and only adverse effects.
Comments on Optimum Length of ADT to support Radiation by Dr. Mack Roach, III, MD
I took a look at some past notes to refresh my memory of studies of ADT in support of radiation, going first to an outstanding presentation.
In 2013 Dr. Mack Roach of UCSF, well known to many of us as one of the world’s top experts on radiation therapy for prostate cancer, delivered a presentation on that topic in Los Angeles in September to the Conference on Prostate Cancer that is primarily for patients.
He addressed many studies bearing on the topic along with his interpretation, including several slides of summary high points and two result-graph slides, both of which he skipped due to the time constraint but provided on the slides DVD. The part of his talk that pertains to length of ADT extends from minute 23’50” to minute 25’53”. The DVD is available at a nominal charge from the Prostate Cancer Research Institute, which was the primary sponsor of the event in collaboration with Us Too.
The bottom line is not different from what we have seen on this board many times, but documented with citations and results from key studies:
— For low-risk men, ADT is not needed. (Indeed, active surveillance is often the best course.)
— For intermediate risk men, a short course of ADT appears optimal (4-6 months).
— For high-risk men, courses of ADT longer than 6 months have proven superior, but with the ideal duration and types of ADT not yet clear.
Expected Nadir with Modern Radiation and Supportive Technology
Allen,
Once again in your report I have run across a study documenting what strikes me as an unexpected and extraordinarily low nadir after modern radiation and supportive technology: 0.05 ng/ml. You reported this for the Anwar study:
“After a median of follow-up of 42.7 months, they reported the following results: ” 5-year biochemical no evidence of disease: 90 percent … PSA nadir (median): 0.05 ng/ml …”
I recall a study from Vancouver where that kind of nadir was achieved, and at least one other study recently; my recollection is that the median nadirs were either 0.05 or < 0.05 ng/ml. My own expectation after "expiration" of the 18 months of ADT3 I had in support of my 2013 TomoTherapy was that I would have a PSA in the tenths, but ever since stopping ADT in April 2014, nearly 2 years ago, my PSA has been < 0.05. My support group buddies who had radiation half a decade to at least a decade ago all had nadir PSAs in the tenths or higher, and my impression until recently was that this was the norm.
Do you still consider nadirs in the tenths as the norm, or has something fundamentally changed?
Jim:
To Allen’s earlier point, Mack Roach’s presentation summary relates to the use of ADT in combination with standard IG/IMRT given over 8 weeks or so. We really don’t know if the same facts apply to the use of hypofractionated radiation therapy given over 5 days. And we won’t know unless there is a randomized, prospective trial … but whether such a trial will ever happen is a whole different question.
Yes, I appreciate the important differences between IG/IMRT over an ~ 8 week course and hypofractionated therapy as you note, but Katz and Kang used durations of ADT that are known to be less effective for high-risk men with the course of about 8 weeks yet generalized that ADT did not make a difference in their series, which is a shaky approach. If they had used durations of ADT ranging from 18 to 24 months, their conclusion might have some credibility. I certainly agree with both you and Allen that a sound trial to put ADT with hypofractionatated RT is needed.
Regarding High Level Evidence for Length of ADT and Risk
Hi Allen,
I’m responding to your statement above, quoted here: “Until we got the results of DART 01/05 last year, we had no high level evidence that long-term ADT was of any benefit when used with escalated doses of IMRT radiation in high-risk patients. In fact, the available evidence that Katz cites in his 2014 paper leaned in the other direction. This once again highlights the importance of randomized clinical trials.”
I and I’m sure all of us would like to see gold standard Phase III clinical trial evidence on this and other issues, but as you note, such evidence is often not available at the time we patients need to make decisions. As a practical matter, well-monitored clinical series with fairly long follow-up can give clues to what we can expect from various tactics, and these series are what Dr. Roach reviews from his expert viewpoint. I can provide his abbreviated references if you wish.
Respectfully, Jim, all Katz and Kang have said is that ADT as used in their study in a relatively unselected group of patients did not make any difference. That is not a generalization. It is simply a statement of fact.
If they had used ADT durations of 18 to 24 months, they would have exposed all these patients to well-understood side effects of ADT that may not have been justified as part of first-line therapy in many of those patients. I would remind you that just a few years ago patients were being given 3 years of ADT because that was the study design originally used by Bolla and his colleagues in men with T2-3N1M0 and T2-3NxM0 disease or otherwise suspected of having micrometastatic disease — a study funded by a pharmaceutical company to show that long-term ADT + relatively low-dose, wide-field radiation therapy was beneficial in that group of patients.
I am all in favor of the appropriate use of ADT when it known to be necessary. However, as we have see the forms of radiation therapy change considerably over time (which we very definitely have) we need to be willing to seriously reconsider the value of long-term ADT in combination with these new forms of radiation therapy given at different dosing levels with far greater accuracy. Many men do not do anything like as well as you have on any form of ADT (in terms of side effects and quality of life) and the survival benefits remain unclear.
What we learn from clinical series is to posit hypotheses that almost invariably need to be tested in well-constructed clinical trials before they are taken as “facts”. Hypotheses are commonly shown to be wrong, or only to be relevant to highly defined subsets of patients.
No one is suggesting that there aren’t patients who benefit from longer-term ADT in combination with differing types of radiation therapy, but the level of clarity about which patients really benefit from how much ADT in combination with which type of radiation is about as murky as the water in the Mississippi delta.
Jim,
While you said “Yes, I appreciate the important differences between IG/IMRT between IG/IMRT over an ~ 8 week course and hypofractionated therapy as you note,” the rest of your statement reveals that you really do not appreciate the important differences. The radiobiology of extreme hypofraction (SBRT or HDR brachytherapy) is very different, and some have suggested that the linear-quadratic model used to project its biological effect should be altered. They argue that extreme hypofractionation may be killing cancer cells in a very different way than conventional fractionation does, perhaps targeting different cellular proteins and the cellular stroma, in addition to the double strand breaks. As one example, it seems that the abscopal effect occurs to a much greater degree with SBRT than with IMRT, and there are clinical trials now for SBRT of bone metastases combined with immunotherapies to take advantage of this unique observation. SBRT also seems to be effective even where there is significant tumor hypoxia. We saw in a commentary last week that local failures may be much less prevalent after SBRT than IMRT. It is not at all clear from any available data that adjuvant ADT adds to SBRT’s effectiveness. Katz’s approach is not “shaky,” it is prudent, given the Demanes study. No one wants to subject patients to unnecessary harms if it can be helped.