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.

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)