SBRT has non-inferior acute and late-term toxicity vs IMRT in two randomized clinical trials

(updated)

In October 2018, the American Society of Radiation Oncologists (ASTRO) strongly endorsed moderately hypofractionated IMRT (20/28 treatments) for primary radiation treatment (see this link). Since then, there has been another publication of a randomized clinical trial with ten years of follow-up (see this link).

The advantages for the patient are large: fewer visits than the conventional 38-44 treatments with a concomitant reduction in costs. Because there is now convincing proof that this can be accomplished without an increase in side effects and without loss of oncological effectiveness, there is no reason why any patient would suffer through the conventional regimen. The remaining question is whether the number of treatments (or fractions) can be reduced even further to only about 4 or 5. This kind of extreme hypofractionation is called stereotactic body radiation therapy or SBRT. This requires proof.

We have seen the results of a Scandinavian randomized clinical trial (RCT) that found that urinary, rectal, and sexual side effects were not inferior with extreme hypofractionation (see this link), and the oncological outcomes were about the same too (see this link).

Now two more RCTs have shown that the toxicity of SBRT is no worse than and possibly better than moderately hypofractionated or conventionally fractionated IMRT.

Van As et al. reported the acute toxicity results of the PACE-B RCT in the UK at the Genitourinary Conference of ASCO. 844 men with favorable risk prostate cancer were randomized to get SBRT (414 men) or conventionally fractionated/moderately hypofractionated  IMRT - "CFMHRT" (430 men). The qualifications were:

• localized, favorable risk prostate cancer (Gleason score ≤ 3+4, Stage T1 or T2, PSA ≤ 20 ng/ml)
• unsuitable for surgery or preferring radiation

The two groups were similar. The treatments were:

• SBRT: 36.25 Gy in 5 fractions over 1-2 weeks
• CFMHRT: 78 Gy in 39 fractions (conventional) or 62 Gy in 20 fractions (moderately hypofractionated)
• ADT was not permitted

At 12 weeks post-treatment, acute grade 2 or higher toxicity was:

• rectal: 10% for SBRT vs 12% for CFMHRT - difference was not statistically significant
• urinary: 23% for SBRT vs 27% for CFMRT - difference was not statistically significant

(Update 9/14/22)

Tree et al. reported the late-term toxicity results of the PACE-B RCT.

At 24 months post-treatment, the worst late-term grade 2 or higher toxicity (RTOG* criteria) was:

• rectal: 2% for SBRT vs 3% for CFMHRT - difference was not statistically significant
• Using CTCAE 4.0* criteria, patients treated on the CyberKnife platform had less toxicity (1%) vs CFMRT (4%) and were better off than patients treated with other linacs (5%)
• urinary: 3% for SBRT vs 2% for CFMRT - difference was not statistically significant
• CTCAE 4.0* urinary toxicity was worse vs. RTOG* urinary toxicity: 12% for SBRT vs 7% for CFMRT
• Patients treated on the CyberKnife platform had no difference in toxicity (6%) vs CFMRT (7%) and were much better off than patients treated in 5 treatments with other linacs (17%)
• Patient-evaluated (EPIC*) moderate/severe urinary bother was worse for SBRT (10%) than for CFMRT (5%)
• Grade 3 toxicity was <1% in all groups
• There was no difference in erectile dysfunction

By 24 months post-treatment, the cumulative incidence of late-term grade 2 or higher toxicity (RTOG* criteria) was:

• rectal: 8% for SBRT vs 8% for CFMHRT - difference was not statistically significant
• CTCAE 4.0* rectal toxicity was worse vs. RTOG* rectal toxicity: 12% for SBRT vs 12% for CFMRT
• urinary: 18% for SBRT vs 11% for CFMRT - difference was statistically significant
• CTCAE 4.0* urinary toxicity was worse vs. RTOG* urinary toxicity: 32% for SBRT vs 20% for CFMRT
• Increased urinary frequency was the type of urinary toxicity most often reported: 10% for SBRT vs 5% for CFMRT

*RTOG and CTCAE 4.0 have different criteria for physicians to evaluate toxicity. EPIC-26 is a questionnaire that patients fill out.

Patients treated on appropriate platforms in high-volume centers had equal or better outcomes. Toxicity was low.

 

(updated 9/30/23) After a median follow-up of 6 years of 874 predominantly (91%) intermediate-risk patients across 38 centers in the UK and Canada, van As et al. reported:

• 95% and 96% were free of biochemical (PSA) failure for SBRT and conventionally fractionated radiotherapy, respectively.
• Grade 2 or worse urinary toxicity was 5.5% and 3.2% (not significantly different) for SBRT and conventionally fractionated radiotherapy, respectively.
• Only 1 patient in each cohort had Grade 2 or worse rectal toxicity.

Poon et al. reported the one year late-term toxicity results of a RCT in Hong Kong. 64 low- and intermediate-risk patients were randomized to get SBRT (31 patients) or conventionally fractionated IMRT - "CFIMRT" (33 patients). The qualifications were: Stage T1 or T2, Gleason score ≤ 7, and PSA < 20 ng/ml.

The treatments were:

• SBRT: 36.25 Gy in 5 fractions over 2 weeks
• IMRT: 76 Gy in 38 fractions
• Intermediate risk patients could optionally have ADT before their radiation.

at 1 year post treatment:

• one grade 3 (serious) urinary side effect was reported in each arm
• rectal grade 1 (mild) or higher: 64% for SBRT vs 84% for CFIMRT - significantly different
• urinary grade 1 (mild) or higher: 93% for SBRT vs 100% for CFIMRT - not significantly different

It is too early to assess if there are any differences in oncological outcomes in these two RCTs.

Survival benefit to debulking the prostate with radiation in men with low metastatic burden

The term "debulking" denotes the radical treatment (via prostatectomy or radiation) of the cancerous prostate after distant metastases have been discovered. This first randomized clinical trial of debulking with external beam radiation found that there was no overall survival benefit.

Results of the STAMPEDE randomized clinical trial were published in the Lancet. Like the HORRAD trial (see below), they found there was no survival benefit to radiation debulking among all newly diagnosed men with metastases (Stage M1). Unlike the HORRAD trial, they utilized higher radiation doses.

Newly diagnosed men were treated with standard of care (which at the time meant ADT and docetaxel in 18% of the men) and were randomized to no radiation debulking or hypofractionated radiation, consisting of either:

• 55 Gy in 20 daily treatments, or
• 36 Gy in 6 weekly treatments (note: this bioequivalent dose is 15% higher)

However it made a big difference in survival if the men were oligometastatic (1-3 distant metastases). After 37 months median follow-up:

• Survival increased by 32% (hazard ratio = 0.68) in 819 oligometastatic men
• 3 yr survival was 81% with debulking vs 73% without debulking
• No survival increase among the 1,120 polymetastatic men (defined as visceral metastases or 4 or more bone metastases with at least 1 outside the axial skeleton)

Survival increases were also noted among men with only pelvic lymph node metastases (N1M0), in whom whole pelvic radiation may be curative.

Adverse events from the radiation were generally mild:

• 5% had grade 3 (serious) or higher acute urinary or rectal side effects
• 4% had grade 3 (serious) or higher late-term urinary or rectal side effects

Based on this and their other randomized clinical trials, men with lower metastatic burden should be treated with ADT+Zytiga or ADT+docetaxel, followed in 2 months with local hypofractionated radiation. Men with higher metastatic burden should be treated with ADT+Zytiga or ADT+docetaxel (it is unknown whether ADT+Zytiga+docetaxel adds any additional benefit). Metastasis-directed therapy is under investigation.

(Update 2/18/2021) Because controversy exists in how to define "low metastatic burden," Ali et al. undertook a secondary analysis of the STAMPEDE trial. They found that the benefit of RT debulking was greatest in two groups:

1. 1-3 bone metastases (M1b) with no visceral metastases
2. Only non-pelvic lymph node metastases (M1a) with no visceral metastases

The survival benefit dropped off after 3 bone metastases. There was no benefit in anyone with any visceral metastases (M1c). Metastases are counted based on conventional imaging (bone scan/CT), so metastases found on PET scans do not count towards the total.

(Update 6/7/2022) Long-term follow-up (61 months) of the STAMPEDE trial, confirmed earlier findings:

• Survival increased by 36% if low burden
• Survival decreased by 11% if high burden (not statistically significant)
• No difference in quality of life

Boevé et al. reported the results of 432 men with bone metastases at 28 centers in the Netherlands from 2004 to 2014 (the HORRAD trial). They had received no previous treatments. They all had PSA > 20 ng/ml at the start of treatment and were under 80 years of age. They were randomized to receive either:

1. Lifelong ADT (an LHRH agonist, starting with 4 weeks of an anti-androgen)
2. Lifelong ADT + external beam radiation therapy (EBRT) 

The EBRT dose was 70 Gy (35 treatments of 2 Gy each) or 57.8 Gy (19 treatments of 3.04 Gy each), which are biologically equivalent. No whole pelvic radiation or brachy boost therapy was given.

After 47 months median follow-up, the median overall survival was:

• 45 months in the group that received ADT + EBRT
• 43 months in the group that received ADT only

The difference was not significant

The authors also looked at survival differences based on:

• Number of bone metastases (<5, 5-15, >15)
• PSA at diagnosis (greater or less than 60 ng/ml)
• Gleason score
• Stage
• Age
• Performance status
• Painful bone metastases

None made any significant difference in survival.

The time to PSA progression was slightly longer among those who received EBRT (15 months vs. 12 months), but the statistical significance vanished after correction for patient characteristics.

These disappointing results conflict with several retrospective database analyses. This once again illustrates that only prospective randomized clinical trials can prove a causal relation, and that observational studies are confounded by the vagaries of patient selection; i.e., patients who receive debulking in actual clinical practice are the ones who would do better anyway. It is worth noting that a similar thing had occurred with breast cancer. Several retrospective studies had suggested that resection of the breast tumor  plus axillary lymph nodes increased survival even when distant metastases were detected. However, Badwe et al. reported that when women were prospectively randomized to that treatment or no such treatment, there was no survival difference.

Because this trial began over a decade ago, it does not include radiation doses now considered to be curative (around 80 Gy). Nor does it include brachy boost therapy, which was shown to be superior to EBRT alone in high risk patients in the ASCENDE-RT randomized clinical trial. It is also unknown what effect whole-pelvic radiation or metastasis-directed therapy might have had, or whether prostatectomy with or without extended pelvic lymph node dissection (ePLND) may have increased survival.

(update 7/3/22) Dai et al. reported the results of an RCT among 200 men with oligometastatic PCa randomized to ADT alone or ADT with debulking the prostate with radiation or surgery (85% had surgery). After a median follow-up of 48 months:

• Radiographic progression was reduced by 57% by debulking
• Mortality was reduced by 56% by debulking
• PSA progression was reduced by 56% by debulking

These clinical trials began before CHAARTED, STAMPEDE, and LATITUDE clinical trials proved that early treatment with docetaxel and abiraterone improves survival in newly diagnosed metastatic men. It is unknown what effect debulking may have in men pre-treated with those systemic therapies.

Many of these unknowns are being explored in current clinical trials. The randomized clinical trial of debulking at 257 US locations will allow for systemic pre-treatments and either EBRT or surgery. This clinical trial in Canada allows for treatment with surgery, HDR brachytherapy, chemotherapy, and SBRT to metastases. This clinical trial in Europe allows for treatment with  docetaxel, and abiraterone. This clinical trial in Germany randomizes patients to prostatectomy + ePLND or best systemic therapy.

Because radiation and prostatectomy have adverse effects, this study should make patients cautious about having any kind of debulking outside of a clinical trial.

Free Randomized Clinical Trial of Ga-68-PSMA-11 PET indicator at UCLA

UCLA is now running a randomized clinical trial of the Ga-68-PSMA-11 PET indicator for men  with a recurrence (PSA≥ 0.1 ng/ml) after prostatectomy who are considering salvage radiation therapy (SRT). They are expanding and adding a control arm to the trial they did earlier (see this link) that found that the PSMA-based PET scan was able to change treatment decisions in about half the men.

Here are the trial details and the contact info:
https://clinicaltrials.gov/ct2/show/NCT03582774

UCLA normally charges $2650 for the PET indicator, so this is an opportunity to save some money. If a patient is randomized to the control group, he may still get an Axumin PET scan when his PSA is confirmed above 0.2 ng/ml, which is covered by Medicare and most insurance. The Axumin PET scan only detects cancer in 38% of patients if their PSA is in the range of 0.2-1.0 ng/ml, while the Ga-68-PSMA-11 PET scan detects cancer in about 27%-58% of recurrent men whose PSA is between 0.2 and 0.5. UCLA recently completed another free clinical trial comparing Axumin to Ga-68-PSMA.

I'm told that the NIH trial of another PSMA PET indicator, DCFPyL, has a waiting list of 2-3 months, and they are no longer taking patients whose PSA is below 0.5 ng/ml. It is possible to pay for PSMA-based PET scans in Germany and Australia. The newest and perhaps most accurate PSMA-based PET indicator, F(18)-PSMA-1007, is in clinical trials in Germany (see this link).

This trial is not open to men who have already had SRT, have known metastases, have had ADT within the last 3 months, or who cannot have radiation for any reason.

Salvage Radiation Dose: Decision-Making Under Uncertainty

A large, well-done, confirmed randomized clinical trial (RCT) is the only evidence that proves that one therapy is better than another. According to current consensus, this is deemed "Level 1a" evidence. But this high level of evidence is seldom available. This is especially true of prostate cancer because it takes so long to achieve acceptable endpoints like overall survival, prostate cancer-specific survival, and metastasis-free survival. Such studies are very expensive and difficult to carry out.

Alexidis et al. analyzed the National Cancer Database for men treated with adjuvant or salvage radiation therapy (SRT) after prostatectomy failure from 2003 to 2012. SRT with doses above 66.6 Gy were labeled "high dose," and SRT with doses above 70.2 Gy were labeled "very high dose." Between 2003 and 2012:

• High dose SRT utilization increased from 30% to 64%
• Very high dose SRT utilization increased from 5% to 11%
• Utilization of high and very high dose rates was greatest at academic centers, lowest at community centers.

The authors decry the fact that this doubling of high dose SRT took place in the absence of RCTs that would definitively establish proof. They point out that the evidence for it is based on observational studies (see, for example, King and Kapp and Ohri et al.), which are fraught with confounding due to stage migration,  selection bias and ascertainment bias. Stage migration was the result of better imaging becoming increasingly available to rule out SRT from patients already harboring occult distant metastases. Also, three randomized clinical trials published in the middle of the observational period convinced many radiation oncologists that earlier SRT led to better tumor control than waiting. Selection bias occurred because the patients selected to get higher doses of radiation were healthier and those whose cancer was less progressed -- they would have done better regardless of the dose. Ascertainment bias resulted from the longer observational period for patients treated in 2003 vs. 2012 - the opportunity for treatment failure increases with the amount of time that has passed. The authors also doubt that biochemical recurrence-free survival (which is what was used in observational studies) is a good enough surrogate endpoint for overall survival. They are right that all these factors may be confounding the previous retrospective analyses, and the only way to know with certainty is to conduct a trial where patients are randomized to receive high or low SRT doses,  and follow patients long enough so that median survival or at least metastasis-free survival is reached in the low dose group.

There has been one randomized clinical trial of SRT dose escalation in the modern era. The SAKK 09/10 trial found little difference in acute toxicity symptoms at 70 Gy compared to 64 Gy, but patient-reported urinary symptoms worsened. Unfortunately, many patients were treated with three-dimensional conformal radiation therapy (3D-CRT), which had higher toxicity than the IMRT in widespread use now. Also, it uses freedom from biochemical failure (not yet reported) as its surrogate endpoint.

So, what is a patient to do in the absence of Level 1a evidence? Should he accept the higher doses with possibly added toxicity and better tumor control, or should he go for a lower dose with possibly less toxicity and less tumor control?

As a compromise, Mantini et al. recently reported 5-year biochemical disease-free survival (bDFS) and other outcomes for patients who received higher dose SRT (70.2 Gy vs. 64.8 Gy) depending on their post-operative pathology. They also may have received (depending on pathology) whole pelvic radiation and adjuvant hormone therapy. Those patients who received the higher dose had equivalent 5-yr bDFS in spite of their worse disease characteristics. Those who received only 64.8 Gy still had a 5-year bDFS as high as 92%. We do not know how many of those recurrent men with favorable disease characteristics actually needed any SRT. They were all treated with 3D-CRT and toxicity was not reported.

The other thing we can do when our information is imperfect is go through the Bradford Hill checklist. It can give us more confidence if we have to make a decision based on less than Level 1 evidence. The factors that ought to be considered are:

• Strength of Association (larger associations are more likely (but not necessarily) causal)
• Consistency of Data (independent studies all lead to the same conclusion)
• Specificity (a very specific population is differentially affected)
• Temporality (the effect has to occur after the cause)
• Biological gradient (too some extent, more drug/radiation dose leads to more effect) 
• Plausibility (one can come up with a plausible explanation)
• Coherence (lab studies demonstrate a plausible mechanism for the observed effect)
• Experiment (has the effect been prevented by modifying the cause)
• Analogy (similar factors may be considered)

Unfortunately, the authors did not refer to Dr. King's more recent analysis of SRT dose/response, which we discussed in depth here. He looked at 71 studies, demonstrating consistency. While it is not Level 1 evidence, it is Level 2a evidence. In it, he observes that the salvage radiation dose response conforms exactly to the primary radiation dose response.  In other words, the prostate tumor is equally radio-resistant whether it is in the prostate or the prostate bed. This increases the plausibility of a dose effect of SRT. What's more, dose escalation was proven to be beneficial for biochemical recurrence-free survival, metastasis-free survival, and freedom from lifelong ADT use, for primary radiation in intermediate risk men by a RCT (RTOG 0126). So, we also have greater confidence in SRT dose escalation by analogy.

RTOG 0126 did not find an increase with higher dose in 8-year overall survival or cancer-specific survival. This calls into question whether these longer-term effects are really useful endpoints if we are to be able to obtain and use the results of any clinical trial in a reasonable time frame.

Dr. King proposed a randomized clinical trial of 76 Gy vs. 66 Gy for SRT. Meanwhile, he is routinely giving his SRT patients at UCLA 72 Gy. Dr. Zelefsky at Memorial Sloan Kettering Cancer Center and other eminent radiation oncologists have also upped the radiation dose to 72 Gy. Such doses seem to be safe and effective, but it is one of many factors in the SRT treatment decision that must be carefully considered by patients and their doctors.

First randomized clinical trial of SBRT

In the first trial ever to randomly assign patients to extreme hypofractionation, primary radiation therapy delivered in just 7 treatments had the same effectiveness and safety as 39 treatments.

The results of the HYPO-RT-PC randomized clinical trial were published in The Lancet. There was an earlier report on toxicity. Details of the trial specs are available here. Between 2005 and 2015, they enrolled 1200 intermediate- and high-risk patients at 12 centers in Sweden and Denmark to receive either:

1. Conventional fractionation: 78 Gy in 39 fractions
2. SBRT (stereotactic body radiation therapy): 42.7 Gy in 7 fractions

The biologically effective dose is 19% higher for SBRT in terms of cancer control. The biologically effective doses are equivalent in terms of toxicity.

The patients were all intermediate (89%) to high risk (11%), defined as:

1. Stage T1c-T3a
2. PSA> 10 ng/ml 
3. Gleason score ≥7

80% of the men were treated with a technology called three-dimensional conformal radiation therapy (3D-CRT), which is seldom used for prostate cancer external beam therapy anymore at major tertiary care centers. It is never used for SBRT in the US because it is considered not precise enough, and too toxic. SBRT is usually delivered in 4 or 5 fractions in the US. CyberKnife and VMAT are the most common technologies in use, and use of sophisticated image guidance throughout each treatment is a common practice.

With follow-up of 1,180 patients for 5 years, they report biochemical recurrence-free survival of 84% in both arms of the study.

They also reported updated late-toxicity results. By 5 years after treatment:

• Grade 2+ urinary toxicity was 5% for conventional fractionation, 5% for SBRT - no significant difference.
• Grade 2+ rectal toxicity was 4% for conventional fractionation, 1% for SBRT - no significant difference.

Up until now, we've only had reports from clinical trials using SBRT (like this one) or conventional fractionation (like this one), and it could have been reasonably argued that SBRT results looked good because of selection bias. With this study, we now have Level 1 evidence of non-inferiority. This will not be surprising to those of us who have followed the randomized clinical trials of moderately hypofractionation vs. conventional fractionation (see this link). This will be hailed as a victory for patients who no longer have to endure and pay the high cost of 8 weeks of treatments. radiation oncologists, who are reimbursed by the number of treatments they deliver, probably will not be as thrilled.

Why did biochemical control not translate into a survival increase after brachy boost therapy?

The first randomized clinical trial to prove that brachy boost (BB) therapy had better oncological outcomes among high risk patients was Sathya et al. (2005). After 5 years, 36% of those high-risk patients who received the brachy boost had a PSA recurrence vs. 66% of those who received external beam radiation (EBRT) only. In an update, the authors report that overall survival was not significantly different in the two groups. This seems to call into question whether PSA recurrence is a useful surrogate endpoint for survival, or if it is, under what circumstances?

Dayes et al. provided a 14-year median update on the original study and added further comments in this "Beyond the Abstract" essay. The 104 patients in the original study who were treated between 1992 and 1997 had the following characteristics and treatments:

• Median age was 66
• 60% were high risk, 40% intermediate risk
• All had a negative pelvic lymph node dissection, negative bone scan and CT
• Brachy boost (BB) comprised 35 Gy of Ir 192 over 48 hours plus 40 Gy of EBRT in 20 fractions for a total of 75 Gy [sic].
• EBRT-only compromised 66 Gy delivered in 33 fractions using 2DRT (an outmoded external beam technology).
• None received androgen deprivation as part of their radiation therapy, nor afterwards unless PSA reached 20 ng/ml.

As of the update on the 104 patients (with only 5 lost to follow-up):

• Mortality from any cause was 67% among the BB patients, 77% among the EBRT-only patients -- not significantly different
• Prostate cancer-specific mortality was 18% among the BB patients, 23% among the EBRT-only patients - not significantly different
• Incidence of metastases was 20% among the BB patients, 28% among the EBRT-only patients - not significantly different
• Improvement in PSA control was maintained: 47% higher rate of biochemical recurrence-free survival among the BB group

There was a biopsy given 2 years after treatment to 87 of the 104 men in the original study

• In the BB group, 24% had a positive biopsy and 6% were metastatic
• In the EBRT-only group, 51% had a positive biopsy and 6% were metastatic

The authors conclude:

Despite ongoing benefit with respect to biochemical disease control, long term follow up out to 2 decades failed to demonstrate improvements in other important outcomes such as development of metastatic disease, deaths from prostate cancer and deaths from any cause. 

Increased biochemical (PSA) control usually translates into increased survival later on. That correlation is well-characterized. So why did it not in this case?

This study, with a sample size of only 104 (51 BB, 53 EBRT-only), was not large enough to detect statistically significant survival differences. We note that directionally there was an improvement in survival even though the difference wasn't big enough for 95% confidence. Also, 40% were intermediate risk patients who are slower to have detectable metastases and are more likely to die of other causes. By contrast, the ASCENDE-RT trial of LDR brachy boost therapy recruited 398 men, 30% were intermediate risk, and may eventually be able to demonstrate overall survival differences with longer follow-up.

We have to acknowledge that the doses delivered in this study were below what is now considered curative, and the findings here are to a large extent irrelevant. I am at a loss to explain how a hot iridium implant could be left in a patient for 48 hrs without doing serious damage or cooking the prostate to a crisp.  Perhaps they used cooler implants back then.  I can only trust that Dr. Sathya is correct in not making a correction for the lack of fractionation, which would be typical. It seems the BB dose was sub-optimal as demonstrated by the fact that in a quarter of men, the cancer was left alive in the prostate. EBRT-only was worse - leaving cancer alive in the prostates of twice as many men. Although they dissected some pelvic lymph nodes that they could find, we now know that even with improved modern lymph node detection methods, we miss 44% of positive lymph nodes (see this link). The 6% who were metastatic might have been caught with some of our new PET scans. So, in both groups, there was a lot of cancer left behind. Many high-risk radiation patients today would have had whole-pelvic radiation and would have had hormone therapy for up to two years. This highlights the importance of expanding the treated area, using escalated doses, and adding systemic therapy when the probability is high that the cancer might have escaped the prostate.

Even though BB wasn't curative for many high risk patients, it is disappointing that death was not delayed by reducing the tumor burden. There are several clinical trials of treating the prostate (with surgery or radiation) even after metastases have been detected, thereby hoping to prolong survival by reducing the load of cancer cells. Metastasis-directed radiation is sometimes given in this hope as well. Both of those therapies decrease PSA, at least temporarily. But only treating PSA serves no purpose if that is the only outcome. If this study is any indication, the cancer will catch up and replace the killed cells with no net survival benefit. I hope that is not the case.

First US randomized clinical trial of oligometastasis-directed SBRT

In a recent commentary (see this link), we saw that some clinicians are making unsubstantiated claims of cancer control from treatment of oligometastases (less than 5 detected metastases). Only a randomized clinical trial (RCT) can prove that there is any benefit to such treatment. Johns Hopkins has announced the first such RCT in the US.

Stereotactic body radiation therapy (SBRT) is the treatment of choice because it is precise, as well as convenient for the patient (usually completed in 1-5 treatments). It is important to distinguish between two different situations that may involve oligometastases:

1. Metastasis-directed SBRT after primary treatment (prostatectomy or prostate radiation) and any local salvage radiation has failed. This is sometimes called "metachronous" treatment of recurrent prostate cancer.
2. Radiation to the prostate and oligometastases in newly-diagnosed men, or men who are radiation- or surgery-naive but have progressed to castration-resistance.
3. Radiation to metastases for the purposes of pain palliation, or to prevent fractures or spinal compression.

In addition, the situation may be different depending on whether the oligometastases are in the visceral organs, bones, extra-pelvic lymph nodes, pelvic lymph nodes, or some combination of these.

Phuoc Tran is the lead investigator of the "ORIOLE" RCT (NCT0268058) at Johns Hopkins described at this link. It is a small, Phase 2 trial for men in situation A described above. It has some noteworthy characteristics:

• 36 men will receive SBRT, 18 men will receive standard-of-care treatment
• Oligometastases are diagnosed by bone scan and CT
• Patients will be balanced based on whether initial treatment was surgery or radiation, whether they've had hormone therapy, and whether the PSA doubling time was less than 6 months.
• The primary outcome will be radiographic or PSA progression (by >25% over nadir and by > 2 ng/ml) after 6 months.
• To be deemed successful, the treatment will have to reduce this measure of progression by 50%

There are several interesting secondary objectives of this RCT:

• identification of additional metastases using the DCFPyL PET/CT
• toxicity of treatment reported by doctors
• pain palliation reported by patients
• local control of metastases (see below)
• Number of circulating tumor cells (CTC)
• Genomic analysis of CTCs
• Immune (T cell) response to treatment
• Time until patients have to start life-long hormone therapy

We will see if the radiation activates a systemic T-cell response that may destroy cancer cells beyond the treated tumors (the abscopal effect).

It may seem odd that detection of fewer than 5 metastases by the DCFPyL PET/CT (developed at Johns Hopkins and now in expanded trials) is not a qualifying criterion. Perhaps they will change that for the Phase 3 trial. Or perhaps they want to prove the concept with a bone scan/CT because it will be several years before that PET scan (so far, the most accurate) is widely available and covered by insurance or Medicare. If it works for bone scan/CT-detected oligometastases, it will certainly work for DCFPyL PET-detected metastases.

Update (August 2017): Dr. Tran has made the following change in protocol:

We did change the criteria recently to allow men who had detectable disease on DCFPyL to enroll on the trial, BUT only if the DCFPyL did not show anything more than what is visible on conventional CT-AP and bone scan.  Our thought was that this would allow some patients of the "future" if you will (as PSMA-targeted imaging will be the SOC in 3-5 years) to be included on the trial, but because we do not allow men on the trial with DCFPyL scans that show us more than what is on conventional , we feel that still holds to original concept. 

It is also important to note what is not an objective of this early clinical trial. The outcome we most want to know is whether SBRT treatment of metastases extends overall survival. This 6-month trial will not tell us that. There is no doubt that local control will be excellent, but stopping the progression of 1-3 metastases does not necessarily mean that the cancer has been slowed down systemically at all. Certainly, PSA will fall as an immediate result of treatment. For those who are used to monitoring PSA as a measure of their cancer's systemic progression, this can be confusing. It's worth taking a moment to recall what serum PSA comes from in detectably metastatic disease. PSA is a protein on the surface of prostate cancer cells (and healthy prostate cells too.) It doesn't leak out into the blood from prostate cancer unless a tumor forms with its own blood supply. Tumor blood supply tends to be leaky, and so PSA is detected in the blood serum. Larger tumors with more blood supply put out more PSA. So irradiating those tumors and shrinking them is likely to eliminate the PSA they put out. But what about the micrometastases that do not yet have appreciable blood vessels? If there are thousands of them, will it matter that serum PSA was reduced for 6 months? No one knows the answer to that question and this Phase 2 study will not provide the answer. I hope they will provide radiographic progression-free survival separate from PSA progression-free survival.

For the answers to our most important questions we will have to look forward to the outcomes of some of the other RCTs that have longer follow-up than 6 months.

• The CORE RCT (active, no longer recruiting) at Royal Marsden Hospital in London will have 5 years of follow-up (completion in 2024), and will include freedom from widespread metastatic disease and overall survival among the outcomes looked at. 
• The STOMP RCT at University Hospital in Ghent had 2 years of follow-up looked at time to lifelong hormone therapy as its primary outcome (reviewed here). 
• The PCX IX RCT (among castration-resistant patients) at Jewish General Hospital in Montreal will have 5 years of follow-up (primary outcome in 2025) and has radiographic progression-free survival as its primary outcome. 
• The French RCT (recruiting, study completion in 2022) will look at radiographic progression-free survival with follow-up up to 3 years. 
• The FORCE RCT at the University of Michigan (primary completion in 2022) will compare systemic treatment with ADT and any of Taxotere, Zytiga or Xtandi (at the discretion of the treating physician) to similar systemic treatment plus metastasis-directed SBRT for men with mCRPC who have not yet had any of those advanced systemic therapies. They will evaluate progression-free survival after 18 months. "Progression" is defined as alive and at least a 20% increase (and at least 5 mm net increase) in the size of tumors or any new metastases. They will detect metastases via bone scan/CT, However, they will also test whether PSMA-based PET indicators are as useful in among men with mCRPC as it is in men with newly  recurrent disease.

Eighth randomized clinical trial of hypofractionated radiation therapy

We now have an eighth randomized clinical trial of hypofractionated radiation therapy. There are no surprises: it showed that oncological and toxicity outcomes were not significantly different between the two regimens. We last looked at it here. This trial is unusual because of the length of follow-up.

Arcangeli et al. report the 10-year outcomes of their study covering 168 high risk patients treated using 3D-CRT (not IMRT) at the Regina Elena Cancer Institute in Rome between 2003 and 2007. The details of the treatments were as follows:

• Half (85 patients) received conventionally fractionated (Conv)  80 Gy in 40 fractions
• Half (83 patients) received hypofractionated (Hypo) 62 Gy in 20 fractions

After a median of 9 years of follow-up:

• 10-year freedom from biochemical failure was 72% for the Hypo group vs. 65% for the Conv group.(no statistically significant difference)
• 10-year prostate cancer -specific survival was 95% for the Hypo group vs. 88% for the Conv group (no statistically significant difference)
• 10-year overall survival was 75% for the Hypo group vs. 64% for the Conv group (no statistically significant difference)
• Hypofractionation was a significant variable in determining prostate cancer-specific survival in multivariate analysis
• There were no differences in late-term grade 2 or higher urinary or rectal toxicity between the 2 groups.

There are a couple of caveats. For those who insist on rigorous analysis, the Hypo group had worse oncological and toxicity outcomes on an intention-to-treat basis. It was only after the patients were analyzed according to the treatment they actually received that the lack of statistically significant difference became apparent. James Yu, in an accompanying editorial, points out that blood in urine was 16.5% for the Hypo group vs. 3.6% for the Conv group. This may be a caution that hypofractionation should not be attempted using 3D-CRT. In the US, where IMRT is widely available, this should not be an issue.

Here's the table summarizing all 8 randomized clinical trials:

Randomized Clinical Trial	Risk Groups	Fractionation	5-yr bPFS	Urinary toxicity Grade 2+	Rectal toxicity Grade 2+	Ref.
PROFIT	100% intermediate	60 Gy/20fx 78 Gy/39fx	85% 85%	22% 21%	8% 14%	1
Fox Chase	67% Intermediate, 33% high	70.2 Gy/26fx 76 Gy/38fx	77% 79%	22% 13%	18% 23%	2
CHHiP	73% intermediate, 15% low, 12% high	60 Gy/20fx 74 Gy/37fx	91% 88%	12% 9%	12% 14%	3
MD Anderson	71% intermediate, 28% low, 1% high	72 Gy/30fx 75.6 Gy/42fx	89%† 85%†	16% 17%	10% 5%	4
RTOG 0415	100% low risk	70 Gy/28fx 73.8 Gy/41fx	94% 92%	30% 23%	22% 14%	5
HYPRO	>70% high, <30% intermediate	64.6 Gy/19fx 78 Gy/39fx	81% 77%	41% 39%	22% 18%	6, 7
Cleveland Clinic	49% low, 51% intermediate	70 Gy/28fx 78 Gy/39fx	94% 88%	1% 2%	5% 12%	8
Regina Elena	100% high risk	62 Gy/20 fx 80 Gy/40 fx	72%* 65%*	21% 14%	NA NA	9

*10-year figures for the Regina Elena trial
† 8-yr failure-free survival update for MD Anderson