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

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.

Salvage Low Dose Rate Brachytherapy (LDRBT) after primary LDRBT failure

Although focal retreatment of the prostate using LDRBT has been used after failure of external beam radiation, there have been very few reports of salvage LDRBT after an initial treatment with LDRBT failed.

In a study at the University of Kentucky (UK), Lacy at al. looked at the records of 21 patients who had been re-implanted with seeds.  They all had a bone scan and CT to rule out metastases and locate areas within the prostate that had less-than-optimal seed coverage. Patient characteristics were as follows:

• ·      Initial low risk: 61percent
• ·      Initially intermediate risk: 29%
• ·      Received EBRT with primary LDRBT: 14%
• ·      Received ADT with primary LDRBT : 33%
• ·      Received ADT with salvage LDRBT: 14%
• ·      Age: 59 (median)
• ·      PSA before primary LDRBT: 6.3 ng/ml (median)
• ·      PSA before salvage LDRBT: 3.5 ng/ml (median)
• ·      Time to biochemical failure: 45 months (median)

Seeds were only added to areas that had poor seed coverage. After 49 months (median) follow-up:

• ·      52% were free from a second biochemical failure
• ·      All of the men who were initially classified as intermediate risk suffered biochemical failure.
• ·      All had an initial decline in PSA, reaching a nadir of 0.7 ng/ml at 15 months (median).
• ·      The remaining 48% exhibited biochemical failure at 25 months (median).
• ·      Urinary symptoms were apparent at 3 months after retreatment but improved back to baseline by 18 months.
• ·      Serious side effects comprised bladder outlet obstruction (1 patient), rectourethral fistula (1 patient), and leiomyosarcoma (1 patient).
• ·      Of the 6 men fully potent at baseline, 5 had some deterioration in erectile function by 18 months after re-treatment.

Several other small studies have demonstrated higher rates of biochemical re-recurrence-free survival (Blasko et al., Koutrouvelis et al., Mahal et al., Hsu et al.). Because of the relatively long time to recurrence after re-treatment (25 months median), those studies probably lacked the length of follow-up necessary to detect the re-recurrence.

As with all attempts at salvage treatment after any kind of radiation failure, two conditions must be met before any such attempt is made:

1.     There must be assurance that the failure is local – in the prostate.

2.     There must be assurance that the cancer has not metastasized outside of the prostate.

Multiparametric MRI-targeted biopsies or saturation biopsies (or the two combined) are best for assuring the first condition is met. A more common option has been a random TRUS-guided biopsy. Some of the newer types of PET scans, such as C11-Choline, are best for assuring that the second condition is met. The more common option is the bone scan with CT.

In the UK study, only bone scans and CTs were used to rule out metastasis, and there were no biopsies done to assure that they were treating a local recurrence. They assumed that there were local recurrences in under-covered areas (“cold spots”). It is likely that their oncological outcomes might have been improved by better patient selection. In the University of California San Francisco (UCSF) study, they used MRI/MRS targeting to biopsy areas for recurrence, and to detect cold spots. Two patients had a second focal brachytherapy re-treatment. Five of the 11 patients failed retreatment at 3 years of followup, but 3 of the 5 had negative biopsy results, indicating that the failure was due to remote metastases. Because of better treatment planning possible with the advanced MRI imaging, UCSF also had minimal treatment-related toxicity. Erectile function was maintained with medication in 67% and without medication in 20%.

Good oncological control after LDRBT failure has been reported using salvage surgery and salvage whole-gland cryotherapy; however, sexual toxicity is high with both, and urinary and rectal toxicity is high with salvage surgery. Salvage focal cryotherapy, as well as other focal ablative therapies may increasingly be used for this purpose. As far as other kinds of re-irradiation goes, there has only been a single case report of salvage SBRT after LDRBT failure. Salvage focal HDRBT may be used for this purpose as well.

written April 25, 2016