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?