SBRT for High Risk Prostate Cancer (update)

One of the more interesting developments in the use of radiation to cure high risk prostate cancer is to use SBRT (see this link). The standard of care remains external beam radiation with a brachytherapy boost. But SBRT, if successful for this purpose, may afford equal oncological outcomes with less toxicity and completion in only 5 treatments.

(update 11/18/2018) Alayed et al. reported the 5-year outcomes of 60 men treated with SBRT (which they call SABR) for high-risk prostate cancer at Sunnybrook Hospital in Toronto. The prospective pilot trial comprised 2 cohorts of 30 men each, treated as follows:

1. 40 Gy in 5 fractions to the prostate + 30 Gy in 5 fractions to the seminal vesicles
2. 40 Gy in 5 fractions to the prostate + 25 Gy in 5 fractions to the seminal vesicles AND the pelvic lymph nodes

12-18 months of adjuvant ADT were used in both groups.

Median follow-up was 5.6 years for Group 1 and 4.0 years for Group 2. The 5-year outcomes were:

• Biochemical failure was 15% in Group 1 and 0% in Group 2
• 4-year PSA was < 0.4 ng/ml for 63% of Group 1 and 93% of Group 2
• Late sexual and rectal side effects were worse for Group 1 than Group 2, urinary side effects were similar

This suggests that SBRT provides oncological outcomes that are similar to brachy boost therapy, while the side effects may be lower, especially if the dose to the seminal vesicles is 25 Gy/ 5 fractions. It also suggests that whole pelvic treatment is probably beneficial in high-risk patients and that toxicity is not higher.


Katz and Kang have presented the largest and longest follow-up trial of SBRT for high risk patients, with 98 patients and 8 years of follow up. Of those, 46 were treated with an SBRT boost following whole pelvic IMRT radiation, and 52 were treated with SBRT monotherapy. The 8-yr biochemical disease-free survival was 61%. This did not differ significantly whether they received the SBRT boost or monotherapy. It also did not differ significantly whether they received adjuvant ADT (55% did). Several different doses were used, but none had significantly better performance. Higher stage and higher grade cancers were cured equally well. Only patients with high initial PSA, perhaps indicative of metastases, fared worse than patients with lower initial PSA. Late Grade 2 rectal toxicity was higher for the combo IMRT+SBRT treatment. Late urinary and rectal toxicity were low (5% grade 2 + 3% grade 3 urinary, 7% grade 2 bowel toxicity), and transient, with none after two years.  This was reflected in patient-reported quality-of-life scores, which declined immediately after treatment but returned to baseline in less than a year.

Kishan et al. presented early toxicity outcomes of the UCLA SBRT trial for high risk patients, which was described here and here. They treated 61 patients, 40 with adjuvant androgen deprivation therapy, 23 also received radiation to the pelvic lymph nodes. ADT and nodal radiation had no effect on toxicity.

After 1 year of median follow-up, the physician-reported toxicities were as follows:

• There were no grade 3 or higher toxicities
• Acute grade 2 urinary toxicity - 13%
• Acute grade 2 rectal toxicity - 7%
• Late grade 2 urinary toxicity  - 7%
• Late grade 2 rectal toxicity - 8%

At 12 months, the percent of patients who reported at least minimally detectable changes were:

• Urinary incontinence: 14%
• Urinary obstructive symptoms: 31%
• Bowel symptoms: 28%

There is also a recent report on SBRT boost therapy for high risk patients (see this link). Paydar et al. reported on 108 patients treated at Georgetown University,  59 of whom were high risk. The toxicities reported were as follows:

• Acute urinary toxicity - 18% grade 2 ,  1% grade 3
• Acute rectal toxicity - 7% grade 2
• Late urinary toxicity  - 40% grade 2, 6% grade 3
• Late rectal toxicity - 12% grade 2, 1% grade 3

SBRT boost therapy seems to increase toxicity significantly more than SBRT monotherapy. We will have to wait for reports of oncological outcomes to see whether the trade-off is worthwhile.

For very high-risk patients, EBRT + BT is superior to surgery or EBRT only (Redux)

In August, Kishan et al. showed a preliminary analysis of oncological outcomes among Gleason score 9 and 10 patients treated with brachy boost therapy (EBRT+BT), external beam radiation therapy alone (EBRT) or surgery (see this link). Because of the limited sample size, some of the differences were not large enough to be statistically significant. Kishan et al. have now expanded their analysis to include 1,001 patients treated between 2000 and 2013, who were treated at several of the top institutions in the US: UCLA, Fox Chase, Cleveland Clinic, Mt. Sinai, and Wheeling Hospital. So far, only an abstract of the study has been presented at the GU Conference. The patient characteristics were as follows: 

• 324 were treated with radical prostatectomy (RP).
• 347 were treated with EBRT only.
• 330 were treated with EBRT + BT (BT was either low dose rate or high dose rate).
• All patients were Gleason 9 or 10 on biopsy.

Treatment specs

• Among the RP patients, 40% had adjuvant or salvage radiation therapy (68 Gy).
• Among radiation patients, 90% had adjuvant ADT
• Median dose of EBRT was 78 Gy.
• adjuvant ADT continued for 18 months, median.
• Median equivalent dose of EBRT+BT was 90 Gy
• adjuvant ADT continued for 12 months.

Oncological outcomes

After a median follow-up of 4.8, 6.4 and 5.1 years for EBRT, EBRT+BT and RP, respectively, the oncological outcomes were as follows:

• The 10-year rates of distant metastases were
  • 39.9% for RP 
  • 34.2% for EBRT
  • 19.7% for EBRT + BT
  • Differences between EBRT + BT and the two others were statistically significant.
• The 10-year rates of prostate cancer-specific mortality (PCSM) were
  • 20.3% for RP
  • 25.2% for EBRT
  • 14.1% for EBRT + BT
  • Differences between EBRT + BT and the two others were statistically significant.

The authors conclude:

Extremely dose-escalated radiotherapy offered improved systemic control and reduced PCSM when compared with either EBRT or RP. Notably, this was achieved despite a significantly shorter median duration of ADT than in the EBRT arm. 

Prostate cancer-specific mortality rates were cut in half by combining EBRT with a BT boost. While this does not prove causality (only a randomized clinical trial can do that) it is highly suggestive that escalated dose can provide lasting cures. There may be good reasons why some high risk patients may have to forgo brachy boost therapy in favor of high dose EBRT or RP with adjuvant EBRT, but for most, brachy boost therapy with ADT will probably be the best choice.

Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high risk patients has declined precipitously from 28% in 2004 to 11% in 2013. If a patient sees anyone other than the first urologist, he often only sees a single radiation oncologist who only informs him about IMRT. In most parts of the US, there is a dearth of experienced brachytherapists.

Better cancer control with radiation vs. surgery in high-risk patients

Researchers at the University of Alabama at Birmingham assigned high-risk patients to receive either external beam radiation therapy with androgen deprivation therapy (RT+ADT) or to receive surgery (RP) with or without adjuvant/salvage radiation. RT+ADT was the clear winner. It’s not a randomized trial, and it is small and retrospective, but it’s worthy of note nonetheless.

Baker et al. reported on 121 patients treated between 2001 and 2014 who were diagnosed with Gleason scores ≥8 (on either biopsy or pathology). 71 patients received RT+ADT according to the following protocol:

• ·      75-77 Gy in 40-42 fractions or 70 Gy in 28 fractions
• ·      All received pelvic lymph node radiation
• ·      Almost all (96%) received ADT for 24 months
• ·      1 patient received adjuvant docetaxel

50 patients who had life expectancies ≥ 10 years, no serious comorbidities, and whose prostate were considered resectable, were offered radical prostatectomy instead of radiation. All patients were seen by both a urologist and a radiation oncologist. Of the 50 RP patients:

• ·      76% also had pelvic lymph node dissection
• o   8±6 lymph nodes were sampled
• o   18% had positive lymph nodes
• ·      88% had adverse pathology: positive margins, seminal vesicle invasion, or extraprostatic extension
• ·      74% were stage T3 at pathology (vs. 4% pre-RP)
• ·      84% were GS≥8 at pathology (vs. 63% pre-RP)
• ·      44% received adjuvant radiation
• ·      24% received salvage radiation
• ·      Those with positive lymph nodes received salvage pelvic radiation
• ·      1 patient received adjuvant docetaxel

After average followup of 74 months for those who originally received RT+ADT and 60 months for those who originally received RP, the 5-year biochemical failure rate was:

• ·      7% for those originally receiving RT+ADT
• ·      42% for those originally receiving RP

The 5-year detection of distant metastases was:

• ·      2% for those originally receiving RT+ADT
• ·      8% for those originally receiving RP

The 5-year use of salvage (permanent) ADT was:

• ·      8% for those originally receiving RT+ADT
• ·      34% for those originally receiving RP

While the researchers did not report on toxicities, it is safe to say that those who received original RP suffered worse toxicities. This is true not only because surgery carries greater risk of incontinence and impotence, but also because 68% of those who originally received surgery received radiation on top of that, and half of those men received ADT with their adjuvant/salvage radiation. Adjuvant/salvage radiation has a worse toxicity profile compared to primary radiation.

The results in favor of initial radiation therapy are particularly impressive because radiation patients in this study had more progressed disease at the time of treatment. They had higher Gleason scores, higher stage, and higher risk of lymph node involvement. They were also considerably older. The results are all the more impressive because the amount of radiation given was low by today’s best practice standards, and because combination therapies of external beam radiation with a brachytherapy boost to the prostate have been proven superior to external beam monotherapy in randomized clinical trials. If anything, the selection bias and treatments in this study should have favored those who were initially surgically treated.

On the other hand, it’s been demonstrated that the limited pelvic lymph node dissection of the surgery patients given in this study is often inadequate to detect the full extent of involvement. They note that they have recently changed their protocol to include extended pelvic lymph node dissection (ePLND) on high-risk RP patients. Sometimes ePLND not only detects the extent of involvement, but may also clear the area of cancer without the need of salvage nodal radiation.  Two additional caveats are that the difference in definitions of biochemical failure and the two years of ADT may affect relative outcomes. However, it is hard to imagine that the long-term effects would enough to change conclusions given the magnitude of the difference.

While this is not the large-scale prospective randomized trial of RT vs. RP that we would like to see, the large variance in outcomes should be considered by anyone trying to decide between radiation and surgery for a high-risk diagnosis.

SBRT Boost Therapy

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 IMRT and an SBRT boost to the prostate?

Anwar et al. reported the outcomes of 48 intermediate and high-risk patients treated with SBRT boost therapy between 2006 and 2012 at UCSF. 71% (34 patients) were high risk, 39% (14 patients) were intermediate risk.

The treatment consisted of:

• ·      IMRT: 45-50 Gy in 25 fractions to the entire pelvis if the risk of lymph node involvement was > 15%, 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 4-6 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-yr  biochemical no evidence of disease: 90%
• ·      PSA nadir (median): 0.05 ng/ml
• ·      2 patients had a PSA bounce over 2 ng/ml, which declined with longer followup
• ·      4 patients had a clinical recurrence outside of the radiation field
• ·      Local control (within the radiation field) was 100%.
• ·      Acute toxicity:

o   Urinary, grade 2: 17%

o   Rectal, grade 2: 10%

• ·      Late toxicity:

o   Urinary, grade 2: 25%; grade 3: 1 patient

o   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.

	Anwar et al. SBRT boost	Katz & Kang SBRT boost	Katz & Kang SBRT monotherapy	Lin et al. SBRT boost
Risk levels treated (# of patients)	Intermediate (14) High (34)	High (45)	High (52)	High (41)
Relative BED*	1.27-1.52	1.13-1.17	1.06-1.13	1.17
ADT used	88%	62%	50%	100%
Biochemical Disease-free survival	90% at 5 years	70% at 5 years	68% at 5 years	92% at 4 years
Late-term urinary toxicity	27%	5%	12%	none

* Biologically Effective Dose for cancer control relative to 80 Gy in 40 fractions

Compared to these other small trials, Anwar et al. used significantly higher effective radiation doses 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 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 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 brachy boost therapy trial and an HDR monotherapy trial in the table below.

	Anwar et al. SBRT boost	ASCENDE-RT LDRBT boost	Hoskin et al. HDR-BT monotherapy
Risk levels treated (# of patients)	Intermediate (14) High (34)	Intermediate (122) High (276)	Intermediate (103) High (86)
Relative BED*	1.27-1.52	1.21	1.21-1.35
ADT used	88%	100%	80%
Biochemical Disease-free survival	90% at 5 years	Int.Risk-94% High Risk-83% at 7 years	Int.Risk-95% High Risk-87% at 4 years
Late-term urinary toxicity	25% Grade 2 2% Grade 3	NA Grade 2 18% Grade 3	19% Grade 2 10% Grade 3

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 randomized comparison 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)

21^st Century Oncology- Scottsdale, AZ, Ft. Myers and Plantation, FL, Farmington Hills, MI, Myrtle Beach, SC (NCT02339948)

Sydney, Australia (NCT02004223)

Gliwice, Poland (NCT01839994)

Poznan, Poland (NCT02300389)

EBRT works better with ADT for intermediate/high-risk prostate cancer

The EORTC trial 22991 compared EBRT + short-term ADT vs. EBRT alone in intermediate and high-risk men. The preliminary report by Bolla et al. was posted at the 2016 GU Conference. There are more details of the clinical trial available here. There were 819 patients in the European multi-institutional study:

• ·      407 received EBRT only, 403 received EBRT+6 months of ADT
• ·      Radiation dose: 70, 74, or 78 Gy (at discretion of each institution)
• ·      Pelvic node radiation: at discretion of each institution
• ·      75% intermediate risk, 25% high risk

After a median follow-up of 7.2 years,

• ·      5-year biochemical progression-free survival was 82.5% with the ADT, 69.3% without it.
• ·      Improvement was irrespective of radiation dose.
• ·      5-year clinical progression-free survival was improved by 7.9 percentage points.
• ·      Late urinary toxicity was 5.9% with the ADT, 3.6% without it (not statistically significant)
• ·      Severe sexual function impairment was 27.0% with the ADT, 19.4% without it (statistically significant)
• ·      Symptoms of hormone treatment, sexual activity and functioning were impaired at 6 months with ADT, but there was no difference at 2 years.

The authors conclude:

“The addition of 6 months of medical castration to primary irradiation improves BPFS and PFS in intermediate- and high-risk localized T1b-cT2a N0M0 prostatic carcinoma with no persistent detriment on HRQOL or sexual function.”

Unfortunately, this preliminary report doesn’t break out the intermediate and high-risk men separately.

We have previously looked at the DART 01/05 clinical trial that proved that at escalated radiation doses, long-term (28 months) androgen suppression improved cancer control better than short-term (4 months), at least for high-risk men. The benefit of longer duration ADT was not established for intermediate risk men at 5-year follow-up.

Nabid et al. focused on intermediate risk men and found a clear benefit to adding 6 months of ADT rather than none (after 10 years of follow-up).

It now seems clear that short-term androgen suppression improves results in intermediate risk men, while longer androgen suppression is necessary in high risk men. It would be helpful to know whether the improvement in intermediate risk men was only among the subgroup classified as “unfavorable intermediate risk.” ADT seems to have a more powerful effect than radiation dose, but it is unclear if that effect is maintained with therapies like SBRT and brachy boost that treat with much higher biologically effective doses. We are getting closer to defining an optimal duration of adjuvant ADT by risk level, and future trials using genetic classification data may provide better definition.

ADT and radiation for first-line treatment of node-positive (N1) prostate cancer (STAMPEDE trial details)

In a previous commentary, we mentioned the early top-line results of the STAMPEDE trial, which demonstrated a benefit to whole-pelvic radiation and ADT for treatment of high risk prostate cancer when positive pelvic lymph nodes have been detected. We now have some additional details.

James et al. analyzed data from the control arm of the STAMPEDE trial. The control arm excluded patients with distant metastases and those who had previous treatment. All patients were high risk and were treated between 2005 and 2014 with a minimum of two years of ADT. At physician’s discretion, some were also treated with RT 6-9 months after the start of ADT. Patients with lymph nodes larger than 10 mm were typically staged as “node positive” (N1). Patient counts for this analysis were as follows:

• ·      N0 and RT – 121 patients – 43% received whole pelvic radiation
• ·      N0 and no RT – 46 patients
• ·      N1 and RT -  71 patients - 82% received whole pelvic radiation
• ·      N1 and no RT -  86 patients

Age, Gleason scores, and performance status were similar in all groups. Pre-treatment PSA was higher in patients who had RT, although the differences were not statistically significant. The planned radiation dose to the prostate and seminal vesicles was 74 Gy in 37 fractions or the equivalent hypofractionated dose. The planned dose to the pelvic lymph nodes was 46-50 Gy in 23-25 fractions or 55 Gy in 37 fractions. Increased doses were allowed if the physician was experienced in delivering nodal doses.

Although overall survival was measured, there was too little mortality as of this interim analysis to be worth reporting. Instead, the authors focused on 2-year Failure-Free Survival (FFS), defined as no biochemical recurrence, and no radiographically-detected progression among survivors. Patients would have been ADT-free for 12-15 months by that point, unless they showed early evidence of progressing.

Among the men with no detected nodal involvement( N0):

• ·      The 2-yr FFS was:

o   96% among men who received RT

o   73% among men who did not receive RT

• ·      Late GI toxicity was:

o   Proctitis: Grade 2: 7%, Grade 3: 2%

o   Diarrhea: Grade 2: 3%, Grade 3: 1%

o   Rectal ulcer: Grade 3: 1%

• ·      Late GU toxicity was:

o   Cystitis: Grade 2: 2%, Grade 3: 1%

o   Hematuria: Grade 2: 3%, Grade 3: 1%

Among the men with detected nodal involvement (N1):

• ·      The 2-yr FFS was:

o   89% among men who received RT

o   64% among men who did not receive RT

• ·      Late GI toxicity was:

o   Proctitis: Grade 2: 8%

o   Diarrhea: Grade 2: 6%

• ·      Late GU toxicity was:

o   Cystitis: Grade 2: 5%

o   Hematuria: Grade 2: 2%, Grade 3: 2%

Although this was a prospective study, patients were not randomized to receive RT or not, so there may be selection bias at work. The higher pretreatment PSA in the patients who did not get RT suggests that they may have been considered to be too far progressed to benefit from radiation. However, the benefit of RT was maintained even after adjustment for pretreatment PSA, age and Gleason score.

The planned radiation dose, 74 Gy, is lower than the 80 Gy now considered to be curative. The dose delivered to the pelvic lymph nodes is still within the standard of care. Although almost half of those with no nodal involvement were treated with whole pelvic RT, there was no analysis of benefit in that subgroup.

RT clearly delayed the time to relapse among high-risk patients, regardless of nodal status. The FFS curves continued to diverge after 2 years, indicating a lasting effect of treatment, at least out to 5 years post-treatment. Long-term toxicity was low among all patients who received RT.

Subject to the above caveat on selection bias, this early analysis indicates that men with high risk prostate cancer, whether they had detected nodal involvement or not, benefited from long-term ADT+RT. As there was little long-term toxicity attached to this decision, there seems little reason to withhold such treatment.

The questions mentioned in our earlier commentary continue to be important:

• What is the most appropriate radiation dose?
• Is there a limit to the number of infected nodes beyond which it is fruitless to use RT?
• Should simultaneous integrated boost RT be used on infected nodes?
• Can SBRT equal or improve the risk/benefit profile over IMRT?
• What is the best timing for neoadjuvant/concurrent/adjuvant ADT?
• Can outcomes be improved with docetaxel?
• Can outcomes be improved with immunotherapy?
• Is whole pelvic RT or ePLND more effective?
• Can staging be improved with new imaging techniques?
• What are the patient risk factors that affect oncological control and toxicity?
• How much of the improved survival is a delay due to cytoreduction, and how much is actual cure?