Showing posts with label salvage SBRT. Show all posts
Showing posts with label salvage SBRT. Show all posts

Wednesday, January 24, 2018

Salvage SBRT after Prostatectomy

UCLA has announced a new clinical trial using SBRT for treating recurrent prostate cancer after failure of initial prostatectomy. This is the third such trial in the LA area, adding to the ones at USC and  City of Hope (no longer recruiting). The advantages to the patient are completing salvage radiation in just 5 treatments, and at a lower cost. But there are many issues that the lead investigators, Amar Kishan and Chris King, explored in a very detailed document that they kindly allowed me to see. The hope is that the increased biologically effective dose possible with extreme fractionation will increase cure rates without adding undue toxicity.

Eligibility

Patients are eligible if they had adverse pathological findings (i.e., Stage T3/4, positive margins, Gleason score 8-10, tertiary pattern 5), or PSA rising over 0.03 ng/ml. They are excluding anyone who exhibits distant metastases on a bone scan (M1) or positive pelvic lymph nodes discovered by dissection (pN1). They are allowing patients with non-surgical evidence of pelvic lymph node invasion (i.e., suspected because of a CT or a PET/CT).

Radiation Dose / adjuvant ADT

The treatment plan is:
  • All patients will receive 34 Gy in 5 fractions to the prostate bed. 
  • There may be a simultaneous boost dose of 40 Gy to any detected tumors in the prostate bed.  
  • Optionally, they will also receive 25 Gy in 5 fractions to the pelvic lymph nodes. 
  • Optionally, they will also receive 6 months of ADT beginning 2 months before radiation begins. 
While whole pelvic radiation and adjuvant ADT improve salvage radiation outcomes on the whole (see this link), they may not be necessary in all cases. A recent analysis suggested that adjuvant ADT only benefits those with post-prostatectomy PSA ≥ 0.4 ng/ml, Gleason score 8-10, Stage T3b/4, and those with high Decipher scores (> 1 in 3 probability of distant metastases in 10 years).

The prostate bed dose is biologically equivalent to 85 Gy using conventional fractionation (about 1.8 Gy per fraction). It is much higher than the typical salvage radiation dose of 67 Gy - 72 Gy in 37-40 fractions. It also exceeds by about 9% the dose used in a trial of moderate hypofractionation (discussed here). At the last ASTRO meeting, Dr. King presented the rationale for increasing the salvage radiation dose (see this link).  At the time, he proposed a randomized clinical trial using a dose of 76 Gy with conventional fractionation. The new protocol far exceeds that dose on the basis of biologically effectiveness, but they will compare outcomes to historical controls. The goal is to achieve a 5-year biochemical recurrence-free survival rate of 72%, compared to the historical level of 56%.

Toxicity

Salvage SBRT isn't just another form of salvage IMRT; IMRT is more forgiving. With IMRT, if there is a small misalignment, it is not a big deal -- the dose per fraction is small enough that a target miss caused by organ motion will not materially affect outcomes and will average out over time.
  • Only devices that continuously track prostate bed motion during, and not just at the start of, each treatment, and that operate with extremely fast treatment times may be able to avoid all of the geographic misses. Image guidance is complicated when there is nothing for fiducials to grab onto.  This becomes an important consideration only at higher dose rates.
  • Although the biologically effective dose (BED) for oncological control is higher with the SBRT protocol, the BED to healthy tissues (which causes toxicity) is lower. 
  • For the tissues that may cause acute toxicity, the BED is a third lower compared to a 72 Gy conventionally-fractionated treatment. In a recent trial of 70 Gy salvage radiation, acute grade 2 and 3 urinary toxicity was 18%; acute grade 2 and 3 rectal toxicity was 18% as well.
  • For the tissues that may cause late-term toxicity, the BED is about the same. Serious late-term toxicity was a rare event when 76 Gy was used for salvage in one study, but late term grade 2 toxicity was about 20% urinary toxicity and 8% for rectal toxicity. It is unknown whether the late-responding tissues of the bowels and urinary tract will suffer increased damage from the higher dose rates after longer follow-up.
SBRT as a primary treatment is different from SBRT as a salvage treatment.  There are also several considerations that arise more in the salvage radiation therapy setting than in the primary therapy setting:
  • The bladder and rectum are no longer shielded by an intact prostate, so they are potentially exposed to greater spillover radiation. The prostate bed without the prostate is highly deformable, and rectal distension can change its shape markedly within seconds during the treatment. This increases the amount of toxic radiation absorbed by healthy tissues.
  • The scar tissue of the anastomosis may become inflamed, leading to a higher risk of urinary retention or tissue destruction.
  • The bladder neck, which may be spared during primary radiation and surgery, receives a full dose during salvage radiation therapy, increasing the probability of bladder neck contracture, urethral strictures, pain and incontinence. These problems may be amplified at higher doses per treatment.
  • Erectile function is probably already impaired from the surgery. Neurovascular bundles, if spared by surgery, are far more exposed during salvage radiation.
We have had a couple of cautionary cases where SBRT toxicity has been extraordinarily high. In one, it was because the delivered radiation dose was too high. In the other, there may have been multiple causes.

There has been a study where conventionally fractionated salvage IMRT with a dose as high as 80 Gy has been used with low toxicity. A recent study using moderate hypofractionation for salvage (51 Gy/ 17 fx) also boasted low toxicity levels among treated patients.

They will monitor both physician-reported toxicity and patient-reported toxicity (urinary, rectal, and sexual). If the rate of grade 3 (serious) toxicity is higher than 20%, accrual will be halted and the study subjected to careful review. If the rate is higher than 30%, the study will be terminated.

Dose Constraints

The investigators have put together a set of very tight dose constraints for organs at risk. Organs at risk include the bladder, the front and back of the rectum, the small intestines, the penile bulb and the femoral head. They also included "point dose constraints": the maximum radiation exposure to even a millimeter of the organ at risk. Because of individual anatomy, it may not always be possible to simultaneously meet all dose constraints. In those cases, the physician will decide if the deviation is material, and if it is, he may lower the dose as low as 30 Gy.

Image Guidance

The prostate bed consists largely of loose and highly deformable tissue. Although some radiation oncologists (e.g., at UCSF) use fiducials or transponders for salvage image guidance, most find that they do not stay in place. This has not been a big issue for salvage IMRT because a few "misses" will not contribute materially to toxicity, but it may be a larger issue for salvage SBRT. One way around this is to have the doctor monitor the position of the soft tissue throughout each treatment, and manually realign the beams whenever the position of the tissues deviates from the planning image. The problem is that  manual realignment is time consuming. The patient is lying on  the bench with a full bladder, which may be difficult to hold in. Also, the more time that passes during a treatment, the more opportunity for bowel motion to occur. The lack of intrafractional image guidance remains a concern in this clinical trial that the investigators are well aware of.

A related issue occurs when the pelvic lymph nodes are simultaneously treated. The lymph nodes may move independently of the prostate bed, so it may be impossible to hit both areas simultaneously with pinpoint accuracy. The investigators are using the pelvic bones as landmarks.

Most importantly, all patients must have a full bladder to lift it up and help anchor organs in place. in addition, enemas are required before each treatment, and if the bowels are at all distended, treatment will be discontinued.

Risks

As with any clinical trial, patients take a risk in trying a new treatment. There is also a learning curve that doctors go through in trying out a new therapy.  I, myself, chose to participate in a clinical trial of primary SBRT when there were only 3 years of reported data. I judged the potential benefits worth the risk for me. It was also important to me that the treating radiation oncologist (Dr.King) had been using SBRT for prostate cancer longer than anyone else. Every patient should be well aware of the risks before agreeing to participate in a clinical trial. Patients who are looking for a shorter duration treatment with less toxicity risk may wish to be treated at the University of Wisconsin or in a clinical trial at the University of Virginia (discussed here).

Sunday, September 3, 2017

Focal salvage ablation for radio-recurrent prostate cancer

When there is a recurrence after primary radiation treatment, it is very tempting to try to identify the site(s) of local recurrence within the prostate and prostate bed and only treat those. The hope is that we can destroy any remaining cancer while keeping toxicity to the bladder, rectum, and neurovascular bundles to a minimum. The alternative to treating just the identifiable recurrence sites (focal or hemi-gland treatment) is to treat the whole gland. We saw that whole gland re-treatment with brachytherapy or SBRT seems to have good oncological and toxicity outcomes. But the standard of care, other than salvage surgery, has been salvage whole gland cryotherapy.

Cryotherapy is one kind of tissue ablation technique - it irreversibly destroys prostate tissue, both healthy and cancerous. Other kinds of ablation techniques include High Intensity Focused Ultrasound (HIFU), Irreversible Electroporation (IRE), Photodynamic Therapy (PDT), and Focal Laser Ablation (FLA). There have been small clinical trials of a few types of salvage focal ablation.

Focal Cryotherapy

Abreu et al. compared outcomes of 25 patients who had hemi-gland cryotherapy to 25 patients who had whole gland cryotherapy between 2003 and 2010.
  • 5-year biochemical failure free rate was 54% in the hemi-gland group and 86% in the whole gland group.
  • New incontinence afflicted none of the hemi-gland group and 13% of the whole gland group.
  • Potency preservation occurred in 2 of 7 in the hemi-gland group, but none of the whole gland group
  • Fistula occurred in none of the hemi-gland group and in one patient in the whole gland group.
Li et al. reported the COLD Registry data on on 91 radio-recurrent patients treated with salvage focal cryotherapy between 2002 and 2012.
  • 3-year biochemical disease-free survival was 72%
  • 5-year biochemical disease-free survival was 47%
  • 4 of 14 patients (29%) had positive biopsies
  • 3 patients (3%) suffered a fistula
  • 6 patients (7%) suffered urinary retention
  • 5 patients (6%) suffered incontinence requiring pads
  • Half of previously potent patients were able to have intercourse.
Weske et al. reported on 55 radio-recurrent patients treated with salvage focal cryotherapy at Columbia University Medical Center between 1994 and 2011.
  • 5-year disease-free survival was 47%
  • 10-year disease-free survival was 42%
While whole gland salvage had very good oncological results, the toxicity was unacceptable. Focal therapy has undoubtedly improved over the years, but oncological results could be a lot better, and potency preservation was poor. Could another kind of focal ablation do better?

Focal HIFU

The Ahmed/Emberton group in the UK reported the outcomes 150 radio-recurrent men treated with focal HIFU between 2006 and 2015.
  • 3-year biochemical failure free survival was 48%
    • 100% for low risk patients
    • 61% for intermediate risk patients
    • 32% for high risk patients
  • 3-year composite endpoint-free survival was 40% (endpoints= PSA recurrence+positive imaging+positive biopsy+systemic therapy+metastasis detected+death from prostate cancer)
    • 100% for low risk patients
    • 49% for intermediate risk patients
    • 24% for high risk patients
  • Complications included: 
    • urinary tract infection in 11%
    • bladder neck stricture in 8%
    • fistula in 2%
    • inflammation around the pubic bone in 1 patient
    • They did not report potency preservation
Focal Irreversible Electroporation (IRE)

IRE or NanoKnife has gained interest because it is less of a thermal-type ablation than cryotherapy or HIFU. (See this link and this one for recent reports on its use as a primary therapy.) It is not FDA-approved for use in the US, so its use is limited to clinical trials. An Australian group working under Phillip Stricker, conducted a pilot test on 18 radio-recurrent patients.

With median 21 month follow-up, Scheltema et al. reported:
  • 85% (11 of 13 patients) had mpMRI-undetectable cancer in the ablation zone
    • 1 had an out-of-field recurrence
    • 1 had a false-positive out-of-field recurrence
  • Biochemical failure-free survival (bFFS) was 83% using the nadir+2 definition and 78% using the nadir+1.2 definition.
  • 80% had biopsy-proven no evidence of disease on follow-up
  • Incontinence requiring pads was suffered by 27%
  • Potency preservation was reported by 33% (2 of 6 patients)
Salvage Surgery

For comparison, it is useful to note the outcomes of salvage surgery in radio-recurrent patients. In a recent meta-analysis, Matei et al. show that the 5-year biochemical recurrence free survival is about 50%. Incontinence rates among patients of surgeons who reported on 25 or more salvage surgeries was 47%. Erectile dysfunction was most often 100% (range 72-100%). Other serious complications included anastomotic stricture (closing off of the urethra where it was re-joined) in 18%, and rectal injury in 7%.

Salvage surgery sets a low bar.

Salvage Whole Gland Ablation

As another point of comparison, we can briefly look at the outcomes of salvage whole gland ablation. In two meta-analyses, Mouraviev et al. and Finley and Belldegrun looked at outcomes of salvage whole gland cryoablation. Focusing on the most recent trials, which used the most recent technology, biochemical failure-free rates ranged from 50% to 74%. In the study with the longest follow-up, Chin et al. reported biochemical failure free rates of 34% at 10 years and 23% at 15 years. Using up-to-date techniques, incontinence rates average 22% and impotence was mostly in the 60-80% range.

Crouzet et al. reported on 418 radio-recurrent patients treated with salvage HIFU from 1995-2009.
The 5-year biochemical failure-free survival was 58%, 51% and 36% for patients who were low-, intermediate-, and high-risk, respectively, before their primary treatment. 42% suffered incontinence requiring pad use, 8% required an artificial urinary sphincter, 18% suffered bladder outlet obstruction or stenosis, 2% suffered a fistula, and 2% suffered pubic bone osteitis. They did not evaluate erectile function, but in primary whole-gland HIFU treatment, about 60% of previously potent men had diminished potency after treatment. We would expect further loss of erectile function after salvage treatment.

Importance of Imaging

Good imaging is critical to the success of any salvage therapy after radiation failure. A full body PET scan with CT or MRI must be used to rule out distant metastases. The newly approved Axumin PET scan, now becoming widely available, has good detection rates (89%) when PSA is above 2.0 ng/ml, as it is at the time of a biochemical recurrence after primary radiotherapy. The biochemical failure-free survival (bFFS) numbers are sure to improve over time due to better selection of salvageable cases.

The other use of imaging is to detect the site of recurrence within the prostate. This may be followed with a multiparametric MRI-targeted biopsy or a template-mapping biopsy to precisely localize the cancer for focal ablation.

Caveats

It is only since multiparametric MRIs and better PET scans became prevalent that researchers realized that up to half of post-radiation recurrences are local (see this link). Therefore, it is relatively recently that investigators started to explore salvage therapies beyond salvage surgery and salvage cryoablation. Consequently, the sample size and the length of follow-up in many clinical trials is too small to draw reliable conclusions. The Chin et al. study demonstrates that treatment failures may not show up for 15 years. Whether those late failures are due to occult metastases or incomplete salvage ablation in that early trial is unknown.

We do not yet have a consensus on how to measure success. Researchers often use the Phoenix criterion (nadir+2) that was developed for external beam radiation. Some argue that the Stuttgart criterion (nadir + 1.2) which was developed for primary ablation therapy is a better measure. Because nadir PSA of 0.5 or less after radiotherapy is prognostic for long-term success, many look for that benchmark. Certainly, follow-up mpMRI and targeted biopsy are prudent steps to take 2 years after salvage ablation. However, it is necessary to have a radiologist and pathologist who are practiced at reading an mpMRI and biopsy, respectively, after both radiotherapy and ablation. There are few in the US who meet that qualification.

Another caveat is technological evolution and the learning curve. Cryotherapy is now using third-generation machines that are increasingly precise at forming "ice balls" while protecting nearby healthy tissue. HIFU is in its second generation, and IRE is relatively new. As technologies evolve and as practitioners gain more experience, we expect to see more complete ablation of the cancer and more sparing of the bladder and neurovascular bundles. Studies with longer follow-up may have used machines that are now obsolete. Studies with short follow-up may reflect practitioners on the beginning of their learning curve.

Focal ablation as primary therapy often (20-30% of the time) requires "re-dos." The retreatment may be necessitated by incomplete ablation within the ablation zone or missed bits of recurrent cancer outside of  the ablation zone. Multiple treatments undoubtedly add to cost and toxicity. Follow-up is too short for most studies to know what the eventual "re-do" rate will be.

Summary Table

Below is a table showing some oncological and toxicity outcomes for select studies of various salvage therapies after primary radiation failure. It is meant to be illustrative only - patient selection varied widely. My main purpose is to help patients understand the wide range of salvage therapies, other than salvage surgery and salvage whole gland cryotherapy, that are now becoming available to them.




Length of follow-up
Number in trial
bFFS
Grade 3 or 4 urinary toxicity
Impotence
Reference
SBRT (whole gland)
2 years
29
82%
6%
60%
1
HDR brachy (whole gland)
3 years
61
60%
2%
NA
2
LDR brachy (whole gland)
3 years
37
60%
NA
NA
2
LDR brachy after LDR brachy (focal)
3 years
15
73%
none
13%
3
HDR brachy
(focal)
3 years
15
61%
7%
NA
4
Cryo (focal)
5 years
91
47%
16%
50%
5
HIFU (focal)
3 years
150
48%
NA
NA
6
IRE (focal)
21 months
18
83%
27%
67%
7
Surgery
50 months average
1407 (32-404 in each)
~50%
65%
72%-100%
8
Cryo (whole gland)
45 months average
1385 (12-121 in each)
50%-74%
22%
60%-80%
9
HIFU (whole gland)
5 years
418
58% LR
51% IR
36% HR
62%
> 60%

Previous articles on the subject of salvage after primary radiation:
Local recurrence (Mayo)
Local recurrence (MSK)
Salvage SBRT
Salvage HDRBT and LDRBT
Salvage LDRBT after LDRBT
Salvage whole gland cryo


Monday, August 28, 2017

After failure of first-line radiation, both kinds of salvage brachytherapy are equally effective

A group of researchers at Memorial Sloan Kettering Cancer Center (MSKCC) reported in 2014 (see this link) on the outcomes of 42 patients with radio-recurrent prostate cancer treated with salvage high dose rate brachytherapy (sHDR-BT). The results were quite good - over two thirds had no evidence of further recurrence as of 5 years, and grade 3 toxicity (serious, requiring treatment) was limited to one patient with late-term urinary incontinence. Kollmeier et al. have now updated their results and compared them with outcomes of men treated with salvage low dose rate brachytherapy (sLDR-BT).

All patients were treated between 2003 and 2015, and all salvage treatments were whole gland, not focal or hemi-gland.

  • 37 patients received sLDR-BT
  • 61 received sHDR-BT
  • 45% received adjuvant androgen deprivation therapy (ADT)
  • All patients were screened for distant metastases with a CT or MRI and a bone scan at least
  • All patients had biopsy-confirmed cancer in the prostate

After a median follow-up up 31 months:

  • 3-year PSA relapse-free survival (RFS) was 60%
  • Both therapies were similar
  • RFS=39% for those with PSA doubling times (PSADT) less than 1 year vs. 72% for those with PSADTs of a year or more.
  • No statistically significant differences in urinary or rectal toxicity between the two therapies: most returned to baseline function.
  • sLDR-BT had a higher rate of acute urinary toxicity
  • Erectile function was not measured because of high rates of pre-existing impotence and ADT usage

In the Fuller study of salvage SBRT (see this link), bRFS was 82% at 2 years, and ADT was not used. NIH will soon begin recruitment for a clinical trial of salvage SBRT (NCT03253744), which includes detection using the DCFPyL PET/CT - the best of the new generation. Dr. Kollmeier mentioned that MSKCC has treated a few select patients with salvage SBRT as well. They are also looking at using a more tailored approach: adding systemic therapy for higher grade recurrences and focal/hemi-gland treatment for less aggressive cases. MSKCC is on the leading edge of using the new generation of PET/MRI scans which will undoubtedly improve patient selection going forward.

Tuesday, August 30, 2016

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%


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?