Salvage SBRT for local recurrence after primary radiation therapy (RT)

This is the second of a two-part commentary. In Part I, we looked at studies that identified the site of failure after primary radiation treatment, and learned that over half of radiation failures, at least for IMRT and LDR brachytherapy (the two most popular kinds of primary radiation) were local (prostate/seminal vesicles) recurrences only. In Part II, we look at how SBRT is being used to treat such local recurrences.

Most of us have heard the oft-repeated aphorism from urosurgeons: If you choose radiation first, you can’t have surgery afterwards. That is what Stephen Colbert would call truthy. It’s certainly true that few surgeons are skilled enough to do that very delicate, painstaking surgery, but there are a handful of very high volume surgeons who have the experience to do it well, and get good results. (See this link.)

Other than a rock-star salvage surgeon, the salvage options after primary radiation fall into two categories: salvage ablation and salvage radiation. Salvage ablation after RT has been mostly limited to cryotherapy, although other kinds like HIFU and laser ablation may prove useful. Salvage radiation after RT has been limited to brachytherapy – either low dose rate (seeds) or high dose rate (temporary implants). IMRT cannot be used after previous radiation because of excessive dose to nearby organs. Salvage therapies may be focal (treating only the site of the recurrence), hemi-gland (treating only the lobe of the recurrence), or whole gland. The wider the treated volume, the greater the chance at cancer control, but the greater the risk of side effects. We now have some early data on salvage SBRT for local recurrences after radiation.

Fuller et al. reported on a prospective clinical trial among 29 patients with biopsy-proven local recurrence. All of them were re-treated from 2009 to 2014 with SBRT.
The inclusion criteria were:

• ·      Screened for distant and nodal metastases with CT or MRI scans
• ·      At least 2 years from primary treatment (Median 88 months)
• ·      Median primary EBRT dose of 73.5 Gy (range 64.8-81 Gy)

o   1 patient had received primary LDR brachytherapy, 1 had prior SBRT

• ·      No lasting side effects >grade 1 from the primary therapy

o   48% had chronic grade 1 rectal or urinary side effects

At the time of salvage, the patient profile was:

• ·      Median age: 73
• ·      Stage at salvage:

o   T1c/T2a: 20 patients

o   T2b/T2c: 8 patients

o   T3: 1 patient

• ·      Gleason score at salvage:

o   GS 6: 6 patients

o   GS 7: 12 patients

o   GS 8: 6 patients

o   GS 9: 5 patients

• ·      Median PSA was 3.1 ng/ml
• ·      7 had relapsed in spite of ADT

The salvage SBRT consisted of:

• ·      The CyberKnife system with fiducials was utilized.
• ·      Prescribed dose was 34 Gy in 5 fractions to the prostate
• ·      Peripheral zone and other areas of the prostate received larger doses
• ·      No treated margin outside of the prostate
• ·      No mention of boost to biopsy-identified areas
• ·      ADT was not used

With a median followup of 24 months:

• ·      PSA decreased to 0.16 ng/ml
• ·      2-yr biochemical disease-free survival was 82%

o   No local failures detected

o   No distant failures detected

• ·      Among the 4 recurrences:

o   3 were GS 6/7, 1 was GS 8/9

o   2 were stage T1c, 2 were stage≥T2b

o   3 had original PSA≤5.0, 1 had PSA> 10.0

o   1 had prior ADT

• ·      Late urinary toxicity:

o   Grade 2: 3 patients (10%)

o   Grade 3: 1 patient (3%) required catheter

o   Grade 4: 1 patient (3%) required cystoprostatectomy

o   The patient with prior LDR brachytherapy had severe urinary toxicity.

o   The patient with prior SBRT had only mild, transient urinary toxicity.

• ·      No acute or chronic grade 2 or higher rectal toxicity.
• ·      Among the 10 previously potent patients, 4 (40%) retained full potency

Fuller is cautiously optimistic, noting the limited sample size and limited length of follow-up. His early findings are comparable to those observed with salvage HDR brachytherapy. While PSA response and the recurrence rate so far are excellent, there are no obvious risk factors that predict failure. While toxicity was acceptable given the high lifetime dose of radiation, there were no obvious predictors of toxicity. The previous radiation dose and time since primary treatment may be important considerations. He notes that salvage radiation of previous LDR brachytherapy patients should be approached with caution.

Zerini et al. report on 32 patients who received salvage SBRT after either primary radiation (in 22 patients) or as a second salvage to the prostate bed after primary prostatectomy (in 10 patients). The patients were treated in Milan, Italy between 2008 and 2013. Among the 22 patients who received salvage after primary radiation, the median PSA was 3.9, and the median age was 73.

• ·       Only 3 patients had been previously treated with brachytherapy.
• ·       C11-Choline PET/CT was used in 88% to identify relapse.
• ·       47% were confirmed by biopsy
• ·       Some received a multiparametric MRI scan as well.
• ·       Patients were re-treated at a median of 115 months from first diagnosis.
• ·       Minimum follow-up was 12 months.

The treatment details for salvage SBRT after primary RT were as follows:

• ·       30 Gy or 25 Gy in 5 fractions to prostate and seminal vesicles
• ·       Treatment margins were 3 mm posteriorly and 5 mm elsewhere.
• ·       36% had adjuvant ADT
• ·       Several treatment platforms were used
• ·       Intra-fractional motion was tracked with fiducials.

After a median follow-up of 21 months:

• ·       12.5% had died
• ·       41% had no evidence of disease
• ·       47% had biochemical or clinical evidence of disease
• ·       38% had clinical progression
• ·       25% had out-of-field progression
• ·       12.5% had local progression

Among the 22 patients re-treated after primary RT:

• ·       Grade 2 acute urinary toxicity: 2 patients (9%)
• ·       No grade 2 or higher late urinary toxicity
• ·       No grade 2 or higher acute or late rectal toxicity

This study used markedly lower radiation doses compared to the Fuller study. That probably explains much of the higher local failure rate observed here – 12.5% vs. 0%. Fuller also more carefully selected eligible patients for his prospective trial compared to this retrospective study, and none were previously treated postprostatectomy. On the other hand, toxicity was extremely low in this study.

(Update 3/2017) Mbeutcha et al. reported on 10 patients treated with whole-gland high dose rate brachytherapy and 18 patients treated with focal SBRT after biopsy-confirmed local failure (and C-11 Choline PET ruled out distant metastases) after primary IMRT. The patients were treated in Nice, France from 2011 to 2015. The radiation dose with 35 Gy in 5 fractions. After 14.5 months of median follow-up among those receiving the focal salvage SBRT, 56% remained free of PSA recurrence.

(update 12/2017) Loi et al. reported on 50 patients treated with focal SBRT after F18 Choline PET and MRI-confirmed local failure after EBRT. The patients were treated at the University of Florence. 11 patients had adjuvant ADT. At 4 months after focal treatment, 80% were free of recurrence.

(update 8/2019) Pasquier et al. reported on 100 patients treated with salvage SBRT for biopsy-proven local recurrence after EBRT at 7 centers in France.

• Recurrence sites were located by mpMRI and choline PET scans. 
• The median dose to the prostate was 36 Gy in 6 fractions. 
• 34% had adjuvant ADT for a median of 1 year.
• Median time to recurrence was 7.5 years

After 29 months of follow-up:

• 3-year (second) recurrence-free survival was 55%
• Acute Grade 2+ rectal toxicity was 0%
• Acute Grade 2+ urinary toxicity was 9% (Grade 3 was 1%)
• Late-term Grade 2+ rectal toxicity was 1%
• Late-term Grade 2+ urinary toxicity was 21%

(update 2/23) Cozzi et al. reported on 20 radio-recurrent men after PET and MRI and biopsy-proven recurrence treated with salvage SBRT+ADT.

• 2 yr PFS was 81.5%
• 4/20 patients had a pelvic lymph node recurrence for which they received further SBRT
• No serious (Grade 3) acute or late-term toxicity
• Grade 2 acute urinary toxicity occurred in 10%
• Grade 2 late-term urinary toxicity occurred in 10%

(update 3/29/2023) Nikitas et al. reported a retrospective study of 11 patients who failed LDR brachytherapy and received whole gland SBRT salvage therapy.

• 3 yr PFS was 70.1%
• Median time to recurrence was 2 years
• Late grade 2 and 3 urinary toxicity were 36% and 9%, respectively
• Late grade 2 and 3 rectal toxicity were 0% and 9%, respectively

NIH is currently running a free clinical trial in which all patients will be diagnosed with a DCFPyL PET scan before and after treatment. Details here.

While salvage SBRT seems to be an excellent re-treatment alternative after local failure of primary radiotherapy, there are many outstanding questions, among them:

• ·       Will these early results hold up with larger numbers of patients and longer follow-up?
• ·       What dose is best for providing cancer control while limiting toxicity?
• ·       Will the low toxicity be maintained among patients who were initially treated with escalated doses? What about patients initially treated with brachytherapy?
• ·       Is there a minimum wait time between treatments?
• ·       What margins and dose constraints are optimal? Can the urethra be better spared?
• ·       Should simultaneous integrated boosts or higher doses be used within areas of the prostate?
• ·       Is adjuvant ADT beneficial?
• ·       To improve patient selection, should more advanced imaging be used to detect distant metastases?
• ·       Is there a role for genetic analysis of local recurrences?
• ·       Should tumor hypoxia be ascertained at biopsy?
• ·       What are the relative benefits of salvage SBRT vs. salvage brachytherapy and salvage ablation?
• ·       Can SBRT be used as a focal or hemi-ablative salvage therapy?

SBRT has equivalent toxicity with 5 treatments and 12 treatments

Lukka et al. reported one-year outcomes of the RTOG 0938 trial designed to test whether SBRT done in 5 treatments of fractions has equivalent and acceptable toxicity compared to SBRT in 12 fractions.

This was a multi-institutional US /Canadian study among 246 low risk men. They were randomly assigned to one of two SBRT treatment regimens:

• Arm 1: 36.25 Gy delivered in 5 fractions twice a week for 2 ½ weeks.
• Arm 2: 51.6 Gy delivered in 12 fractions 5 days a week for 2 ½ weeks.

These doses are approximately equivalent in biologically effect for cancer control and in their expected effect on healthy tissues. Men were allowed to be treated on several different SBRT platforms, including CyberKnife, VMAT and protons.

This is the planned 1-yr quality-of-life analysis, with future analyses to be performed after 2 and 5 years.  The EPIC questionnaire was used to assess bowel, urinary, and sexual quality-of-life.

•     Bowel changes > 5 points are considered clinically significant.

o   Any such change affecting ≤ 35% of men was considered to be acceptable.

o   Any such change affecting ≥ 55% of men was judged to be unacceptable.

•   Urinary changes  > 2 points are considered clinically significant.

o   Any such change affecting ≤ 40% of men was considered to be acceptable.

o   Any such change affecting ≥ 60% of men was considered to be unacceptable.

• Sexual score changes ≥ 11 points are considered clinically significant

After 1 year of follow-up, patient-reported clinically significant changes were noted in:

• Bowel changes were acceptable: 29.8% in Arm 1 and 28.4% in Arm 2
• Urinary changes were borderline acceptable: 45.7% in Arm 1 and 42.2% in Arm 2
• Sexual score changes: 32.9% in Arm 1 and 30.9% in Arm 2
• Disease-free survival at two years: 93.3% in Arm 1 and 88.3% in Arm 2
• None of the differences between Arm 1 and 2 were statistically significant

Physician-reported toxicities were as follows:

• Acute urinary: Grade 3 – 2 patients (1.7%)
• Acute rectal: Grade 3 – 2 patients (1.7%), Grade 4 – 1 patient (1.1%)
•  Late urinary: Grade 3 – 1 patient (0.8%)
•  Late rectal: Grade 3 – 2 patients (1.7%)

Both treatment regimens substantially met the study’s toxicity requirements, and confirm that 5 fractions are as toxicity-free as 12 fractions. These outcomes are in line with historical controls based on conventional IMRT treatment regimens. Of course, only a randomized clinical trial (like this one, which proved there were no differences in oncological or toxicity outcomes) can compare IMRT and SBRT.

9-year SBRT outcomes

Katz and Kang have posted their 9-year SBRT outcomes on 515 patients. This represents the longest tracking of SBRT outcomes -- just one year short of the IMRT tracking reported by Alicikus et al. on a starting cohort of 170 patients treated at Memorial Sloan Kettering Cancer Center.

The patients were treated between 2006-2010 using the CyberKnife platform.

• ·      324 were low risk, 139 intermediate risk, and 52 were high risk according to NCCN definitions.
• ·      70 patients received adjuvant ADT for up to one year.
• ·      158, all with Gleason score<4+3, received 35 Gy in 5 fractions.
• ·      357 received 36.25 Gy in 5 fractions
• ·      Median age was 69
• ·      Median PSA was 6.5 ng/ml

After a median followup of 84 months:

• ·      Oncological Control:

o   9-yr freedom from biochemical failure was:

§  95% for low-risk men

§  89% for intermediate risk men

§  66% for high-risk men

o   Median PSA nadir was .1 ng/ml

o   No difference in biochemical control for the lower vs. the higher radiation dose.

o   99.6% prostate cancer survival

o   86% overall survival

• ·      Toxicity:

o   Late rectal toxicity:

§  Grade 2: 4%

o   Late urinary toxicity:,

§  Grade 2: 9.5%

§  Grade 3: 1.9%

§  Grade 2 or 3: 6.9% for the lower radiation dose vs. 13.2% for the higher dose.

o   Patient-reported bowel and urinary quality-of-life (EPIC questionnaire) declined at one month then returned to baseline by 2 years. Sexual quality-of-life declined by 29% at last followup.

These are clearly excellent results for any kind of radical therapy. The authors conclude:

“These long-term results appear superior to standard IMRT with lower cost and are strikingly similar to HDR therapy.”

While it’s tempting to conclude that neither the higher dose of radiation, with its greater toxicity, nor the addition of ADT conferred any incremental benefit, that can only be proved with a randomized clinical trial. Until so proven, it must be understood as only a good hypothesis to be discussed by patients with their radiation oncologists. It is also worth noting that these reflect the outcomes of one very expert practitioner. There is an SBRT registry currently collecting data across many treatment centers.

The reported outcomes are nearly identical to those reported at 7 years (see this link and this link and this link), indicating very stable control and no additional late term toxicity with longer followup. In light of that, its low cost, convenience, and the fact that the standard of care, IMRT, has only one more year of follow-up on a much smaller sample size, it’s difficult to understand why some insurance companies still balk at covering SBRT for low and intermediate risk patients. Medicare does cover it.

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?

The multi-factorial nature of SBRT safety

In a previous article, we looked at the experimental use of extreme hypofractionated radiation therapy, SBRT or SABR, to treat high-risk patients. Here, we take a closer look at an early safety study by Bauman et al. that shows why radiation safety is more complicated than just setting the treatment dose.

Bauman et al. treated 15 high-risk men who were either frail and elderly, or who refused a long course of IMRT. They were all given 12 months of ADT beginning 2 months before SBRT.

After 6 months of follow up, the following rates of genitourinary (GU) and gastrointestinal (GI) toxicity were observed:

• ·      Acute GU toxicity: Grade 2: 27%, none higher
• ·      Acute GI toxicity: no Grade 2 or higher
• ·      Late-term GU toxicity: Grade 2: 33%, Grade 3: 7%
• ·      Late-term GI toxicity: Grade 2: 27%, Grade 3: 20%, Grade 4: 7%
• ·      Toxicity was not correlated with patient frailty

All of the toxicities were higher than expected, and the high rates of high-grade late-term GI toxicity were particularly troubling. As a result, the treatment plans have been altered. They eliminated the dose to the pelvic lymph nodes entirely, extended the ADT treatment to 18 months, and reduced the dose to the prostate to 35 Gy across 5 treatments, with only one treatment per week. This is similar to the plan that Dr.Katz has been using for his high risk patients with 6 years of reported follow up with very low rates of toxicity (see Katz and Kang 2014).

Dr. King has been using the same prostate dose that Dr. Bauman used -- 40 Gy across 5 treatments (NCT02296229). Dr. King has used this dose for all his patients (not just high-risk ones) since 2008 with low rates of toxicity, and he is now treating pelvic lymph nodes on select high-risk patients with 25 Gy. Both King and Bauman use an arc radiation therapy machine, although the brands they use differ – Varian and Elekta, respectively. So what accounts for the very different toxicity outcomes they are getting? Let’s look a little closer.

The following table highlights key dosimetric differences between King and Bauman’s high-risk SBRT protocols.

	Bauman	King
Prescribed dose to prostate	40 Gy (8 Gy x 5)	40 Gy (8 Gy x 5)
Margin treated	5 mm all around	5 mm, except 4 mm posterior
Prescribed dose to SV	40 Gy (8 Gy x 5) in first cm of SV	25 Gy (5 Gy x 5) to entire SV
Margin treated	5 mm	No margin
Pelvic lymph nodes	25 Gy (5 Gy x 5)	25 Gy (5 Gy  x 5)
Margin treated	5 mm	none
Bladder dose constraints:	≤50% receives >29 Gy ≤30% receives >35 Gy	<10 cc receives >25 Gy Max. point dose= 40 Gy
Rectal dose constraints:	≤50% receives >27 Gy ≤20% receives >35 Gy	<5 cc receives >25 Gy Max. point dose= 42 Gy (additional specific constraints for each side of the rectal wall)
Small bowel dose constraints:	<2 cc receives >27.5 Gy <190 cc receives >25 Gy	<10 cc receives >20 Gy Max. point dose= 25 Gy
Imaging for planning	CT	CT/MRI fused images
Inter-fractional motion tracking	Cone beam CT	Cone beam CT with fiducials
Intra-fractional motion tracking	none	Stereoscopic X-rays. Fiducials were realigned every half-arc, approximately 40 seconds.

In comparing the treatment parameters of the two plans, we begin to see why the original Bauman plan would have greater toxicity in spite of the fact that the prescribed dose to the prostate was the same. Perhaps the single biggest drawback to the Bauman plan was the lack of tracking of intra-fractional motion. The prostate can move quite a bit during the treatment. With the low doses of IMRT (1.8-2.0 Gy each) it would not matter so much, but with the higher SBRT doses (8 Gy each), significant amounts of radiation may inadvertently hit the bladder and rectum if the motion is not controlled for.

The other advantages of the King plan include:

• ·      Smaller margins where the prostate abuts the rectum
• ·      No margins around the pelvic lymph nodes that could impact the small bowel
• ·      No margins around the seminal vesicles that might hit the bladder neck
• ·      Tighter bladder and rectal dose constraints
• ·      MRI for more precise planning
• ·      Fiducials for more precise image alignment
• ·      Alignment is frequent and automatic. It’s not dependent on human intervention.
• ·      Optional selection of patients suitable for nodal radiation (e.g., no anatomic abnormalities, presence of visceral fat, high risk of nodal involvement)
• ·      Only 9 months of optional ADT are used

Dr. King has so far treated 19 high-risk patients on his protocol, 10 with nodal radiation. So far there have been no Grade 3 or higher toxicities of any kind. King uses Varian’s Truebeam with RapidArc and realigns four times during each fraction. The total treatment time is about 5-10 minutes each, with hundreds of beams emitted during each 40 second arc. Accuray’s CyberKnife, the most prevalent platform for SBRT, realigns the beams with the fiducials every few beams, and there are hundreds of beams. That extends the treatment time to about an hour each. While many different brands of linear accelerator platforms and image-guidance systems can be used for SBRT, it is vital that continual motion tracking or prostate stabilization (e.g., using a rectal balloon) be incorporated.

Other clinicians have sought the optimal SBRT treatment dose while all the other treatment parameters are held constant. Katz et al. (2011) tried two different doses, 36.5 Gy and 35 Gy, and found the lower dose had similar oncological results. While urinary toxicity was lower for the lower dose in a matched pairs analysis, the difference was not statistically significant. In contrast to Katz,  Bernetich et al.  found that there was a better oncological response to higher doses (37.5 Gy) for higher risk patients, but they also observed an increase in persistent GU toxicity, while GI toxicity remained low and unaffected by dose.  In a study that I consider to be of questionable ethics, Kim et al. experimented with SBRT doses as high as 50 Gy to find the SBRT dose limit for rectal tolerance, and not unexpectedly, found very high amounts of rectal toxicity associated with it. Currently, Dr. Zelefsky is the lead investigator on clinical trial at Memorial Sloan Kettering Cancer Center where he is raising the dose incrementally in successive cohorts of low and intermediate risk patients after insuring the safety of each lower dose. He has so far raised the SBRT treatment dose as high as 45 Gy. Clearly, there are many factors that affect SBRT toxicity, and there are still many details to be learned about SBRT dosimetry.

 note: Thanks to Dr. King for supplying the details of his protocol for high-risk patients and his update so far.