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%	10

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

Most of the recurrences after primary radiation failure are salvageable

Salvage therapy is curative in about half of men who have a biochemical failure after primary therapy. That's true whether the primary therapy was surgery or radiation. It's true when the salvage therapy was radiation after surgery. And it's true whether the salvage therapy was surgery, cryotherapy, or brachytherapy after radiation. Salvage success rates can be as high as 3 in 4, in certain well-selected patients treated with appropriate therapies (see this link, for example), but it can be a lot lower too. Salvage therapy always increases the complications over what they were for the primary therapy, so we would avoid it if we knew it was likely to be futile. Thanks to the new generation of PET scans, we are beginning to understand why, and what we may be able to do to improve those odds.

For any salvage therapy to be effective, two conditions must be met:

1.  The recurrence must be local. Local means in the prostate, seminal vesicles, the prostate bed, nearby organs (e.g., bladder, rectum, etc.), and/or in the pelvic lymph nodes.
2.  The recurrence must not be distant. Distant means metastases in the bones; remote organs like the lungs, liver, or remote lymph nodes; or in systemic circulation in the bloodstream.

In the past, it has been difficult to ascertain that both conditions were met. Bone scans are not very reliable when the PSA is below 20 ng/ml, and they are not specific for metastases. Moreover, by the time the PSA increases that much, the cancer is almost certainly distant and incurable. The NaF18 PET/CT scan can detect metastases sometimes at a PSA as low as 4 ng/ml, but it only detects bone metastases, and it is not specific for metastases. An Ultra-Small Superparamagnetic Iron Oxide (USPIO) MRI may sometimes detect metastases, but only in lymph nodes.  A multiparametric MRI may sometimes detect local recurrences, and may be used to target areas for biopsy in the prostate and prostate bed. It may be reliable after primary radiation (see this link). However, it tells us nothing about distant metastases.  CT scans only detect the larger lesions that may be suspect. A transperineal template mapping biopsy may detect prostate cancer in the prostate, but tells us nothing about distant metastases. It should be noted that biopsied prostate tissue looks very different after radiation, and it should be analyzed by highly experienced pathologists.

Clinical trials have proved that adjuvant radiation after prostatectomy has better outcomes than waiting, and recent studies suggest that overtreatment may be avoided by using early salvage radiation rather than adjuvant radiation therapy. Perhaps early salvage therapy after primary radiation therapy may have improved outcomes too. That is, it may be more successful if started before the patient's PSA reaches the nadir+2 level, which is the official definition of biochemical recurrence after primary radiation therapy.

The FDA-approved C-11 Choline PET/CT (or the similar C-11 Acetate PET/CT) fills some of the critical information gaps. It can detect prostate cancer in the radiation-treated prostate, the local area, and throughout the entire body at a PSA as low as 2 ng/ml, especially if the PSA has been rapidly rising. However, its sensitivity is not very good for small sites of cancer (they must be larger than 5mm), or cancer in lymph nodes. And when used to detect cancer within the prostate, prostatitis and BPH may generate false positives. Some of the new experimental PET scans (e.g., DCFPyL) may be more sensitive. Now that we have an adequate tool for detecting both of the above-mentioned conditions (local and not distant), we are beginning to be able to select which recurrences can be cured with salvage therapy, and which can only be managed with lifelong hormone therapy.

Parker et al. report on the Mayo Clinic experience with 184 patients with rising PSAs after primary radiation therapy on whom the C-11 Choline PET/CT was used to detect local and/or distant prostate cancer progression.

• 87% of patients were PET-positive.
• The C-11 Choline PET/CT correctly identified 98% of patients who were later found to have residual prostate cancer on subsequent histological analysis. 
• However, 42% of patients that were identified as negative by the C-11 Choline PET scan later suffered from cancer progression - they were false negatives.
• Patients were especially likely to be PET-positive if they had higher pretreatment PSA, were high risk, had higher PSA level at the time of the PET scan, had a greater increase from nadir PSA, had a shorter PSA doubling time, and had a higher PSA velocity. All of those with PSA≥ 10 ng/ml were PET-positive.
• Risk category, PSA increase from nadir, and time since primary radiation therapy were independently associated with PET-positivity, and can help predict when recurrences are salvageable.
• 59% of PET-positive patients were confirmed by histological analysis (either biopsy or salvage prostatectomy). 76% were confirmed by a multiparametric MRI.
• 46% of those who were PET-positive had cancer only in the prostate and seminal vesicles. These patients were potentially salvageable with any of the salvage therapies mentioned above.
• An additional 16% (62% in total) had cancer in the soft tissue pelvic region. These may be salvageable with extended pelvic lymph node dissection (ePLND) or radiation in select areas of the pelvis that were not treated originally.
• While only a few patients (21) had a PET scan before their PSA reached nadir+2, half of them had a local recurrence only, and are potentially salvageable. This suggests that the  patient does not have to wait for nadir+2. However on this small sample, the salvageability does not seem to be very different for those who detect it earlier.

This study confirms the findings of the larger study at Memorial Sloan Kettering (MSKCC) (reviewed at this link).  In that study, 55% had a recurrence in the prostate and/or seminal vesicles only, compared to 46% at Mayo. At MSKCC, an additional 8% had recurrences in the pelvic lymph nodes only, compared to 16% at Mayo. There were important differences between the studies. At Mayo, unlike MSKCC, patients may have had brachytherapy as all or part of their primary therapy, they may have had enlarged lymph nodes from the start, they had significantly lower doses of radiation (76 Gy vs ~80 Gy), they were younger (65 vs 69), fewer had adjuvant hormone therapy (30% vs 54%), they all had rising PSA but not necessarily nadir+2, and they all received a C-11 Choline PET/CT, there was less histological confirmation (59% vs 71%), and the median follow-up time was shorter (68 months vs 83 months).

As noted in the commentary of the MSKCC study, these findings may not apply when the primary therapy used a very high biologically effective radiation dose, such as with brachy boost therapy, SBRT, or high dose rate brachytherapy.

It makes sense to rule out the possibility of distant metastases using an advanced PET scan. Even at a cost of $2,500 or so, it may save the patient much more than that for the cost of salvage therapy. However, unless the PET scan is done at Mayo using C-11 Choline, is done as part of the clinical trial using the newly FDA-approved PET indicator fluciclovine, or is one of the free ones at NIH, the out-of-pocket cost may be formidable. Hopefully, the FDA will approve more of them, and availability will expand. Unfortunately for those considering early salvage after a prostatectomy failure, none of them are accurate for PSAs that low (≤0.2 ng/ml).

The authors constructed a nomogram to help the prospective patient predict whether his recurrence, detected with a C-11 Choline PET/CT, is likely to be a salvageable recurrence or unsalvageable recurrence. In the first table, fill in the number of points that comes closest to your situation, and add them up. In the second table, look up the probability of a distant recurrence (unsalvageable) that comes closest to your total number of points.

Risk Factor	Points to assign	My Points
PSA increase from nadir	2 ng/ml: 13 5 ng/ml: 32 10 ng/ml: 63 15 ng/ml: 95
Years since RT	1 yr: 100 2 yrs: 95 3 yrs: 90 5 yrs: 80 10 yrs: 52 20 yrs: 0
Risk Group	Low: 0 Intermediate: 8 High: 45
	TOTAL

My Total Points	Probability of recurrence outside of the pelvic area
66	5%
88	10%
120	25%
153	50%
185	75%
216	90%
240	95%

This nomogram outperformed using a PSA threshold alone in its predictive power, and may help the patient decide whether potentially-curative salvage therapy or lifelong hormone therapy is the better course of action.

I'm not sure why radiation dose was not significantly correlated with the site of recurrence at Mayo (p = 0.1) as it was in the MSKCC study. In fact at MSKCC, those who received doses of at least 79.2 Gy had half the rate of recurrence compared to those who only received 75.6 Gy (which seemed to be the norm at Mayo). It may be that those who were treated at Mayo only received higher doses when their cancer was already systemic. We know that this is on the steep part of the dose/response curve where even a small increase in dose can increase its effectiveness greatly. Whatever the reason for the data discrepancy, higher doses do prevent local recurrences.

(update 11/18/2018) Hayman et al. reported on 49 men who had a biochemical recurrence after whole pelvic primary radiation therapy and long-term ADT who were clinically staged as node positive (N1) via MRI. Using imaging (probably a PET/CT scan) they found the site(s) of recurrence in 46 of the men:

• 25 (54%) had a recurrence in the prostate only
• None had a recurrence in lymph nodes only
• 21 (46%) had a recurrence that included a distant metastasis

This is very similar to Mayo and MSK.

note: Thanks to Dr. Will Parker for letting me review the full text of his published study.

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?