Record 10-year SBRT study among low risk patients

Alan Katz has now published the study with the longest-running follow-up of any study of external beam radiation therapy for prostate cancer among low risk patients, in this case, using SBRT. 10-year follow-up among intermediate and high-risk patients will be presented at next year's ASTRO meeting. This study ties in longest length of follow-up with the Memorial Sloan Kettering (MSK) study of IMRT. IMRT involves 40-45 radiation treatments over the course of about 9 weeks; SBRT shortens the number of treatments to 4 or 5 over the course of about 11 days.

Focusing on their low risk cohort only, the Katz study has a distinct advantage over the MSK study in sample size:

• The Katz study started with 230 low risk patients and, because of later start dates and some loss to follow-up, had 57 evaluable low-risk patients who were tracked for 10 years.
• The MSK study started with 49 low risk patients and, because of later start dates and loss to follow-up, ended with only 2 patients tracked for 10 years.
• Median follow-up was 108 months for Katz and 99 months for MSK

The IMRT study used a prescribed dose of 81 Gy in 45 fractions. The Katz study used a dose of 35 Gy in 5 fractions on 42 patients and 36.25 Gy in 5 fractions on 188 patients (average = 36 Gy). The biologically effective dose for cancer control was 17% higher in the Katz study.

It is risky to compare SBRT and IMRT when patients are not randomized to treatment with one or the other. There has been such a randomized trial, and partial results have been reported (see this link). The median age was the same in both studies (69 years of age), and the same definitions for the low risk category, and for biochemical failure were used. To highlight some of the differences and similarities in outcome:

• 10-year biochemical disease-free survival was 94% for Katz vs. 81% for MSK
• 10-year distant metastasis free-survival was 98.4% for Katz and 100% for MSK
• No prostate cancer-related deaths at 10 years in either study

Late-term urinary and rectal side effects were infrequent and mild in both studies:

• Late-term urinary side effects:
• Grade 2: 9%, Grade 3: 3% in the Katz study
• Grade 2: 9%, Grade 3: 5% in the MSK study
• Late-term rectal side effects:
• Grade 2: 4%, Grade 3: 0% in the Katz study
• Grade 2: 2%, Grade 3: 1% in the MSK study

Of those who were previously potent before radiation, 56% were potent (sufficient for intercourse) 10 years later (median age 79) in both studies.

Other interesting outcomes of the Katz study included:

• Median PSA fell to 0.1 ng/ml after a median of 48 months
• 21% experienced a PSA bounce along the way.
• Cure rates were independent of whether patients received 35 Gy or 36.25 Gy
• Urinary toxicity was higher in the group that got the higher dose
• Rectal toxicity was no different in the two groups
• Patient-evaluated urinary and rectal function declined acutely but returned to baseline within a year
• Sexual function declined by 23% at 6-12 months, and continued to decline by 38% by 8 years. It is unknown what percent of that decline was age related (but see this link).

Looking at the higher local control rates of SBRT and HDR brachytherapy, Dr. Katz sees evidence that IMRT is sub-optimal in delivering biological effective dose. He also believes that no more than 35 Gy in 5 fractions is necessary to achieve that control, and that it would minimize side effects.

Of course, probably half of the low risk men in this study might have gone those ten years without needing any kind of treatment at all. But for those who may not want or may not be good candidates for active surveillance, SBRT is a low cost, low bother, low side-effect alternative that delivers high rates of long-term oncological control.

Amazingly, I still hear that there are insurance companies that will not cover SBRT because longer follow-up is needed. Dr. Katz had already reported the nine-year follow-up (see this link), and with this addition and the 10-year higher-risk update at ASTRO next year, it's hard to see what any objection might be.

Dr. Katz is to be congratulated for continuing to update his study for 10 years. It is a lot of work to follow up with so many patients, and collect and tabulate their reported outcomes. He is a radiation oncologist not associated with a large tertiary care facility that might have more resources at its disposal.

A new Lu-177-PSMA ligand has good results in a new study

Targeted nuclear medicine has shown some impressive outcomes in several small studies, mostly conducted in Germany. Most of the studies have used a radioactive beta-particle emitter, Lutetium 177, attached to a ligand that has high and specific affinity for prostate cancer cells. Most medicines developed for this purpose have a ligand that attaches to Prostate-Specific Membrane Antigen (PSMA), a protein found on 90% of all prostate cancer cells. The ligand for Lu-177-PSMA has to have a "grappling hook" on one end (called a chelator) that holds onto the Lu-177. On the other end is a "magnet" of sorts that binds tightly to the PSMA. The beta particles then kill the cell that the ligand attaches to and some nearby cells as well.

There are also ligands that attach to prostate cancer proteins other than PSMA, and radioactive elements other than Lu-177 that are in clinical trials. This is a rapidly developing field.

The new ligand is called PSMA-I&T (imaging and therapy) or sometimes PSMA-DOTAGA. The ligand used in most of the other studies was PSMA-617 (also known as PSMA-DKFZ) or PSMA-J591. The ideal ligand attaches strongly to PSMA in prostate cancer tumors and to nothing else. Importantly, it should not accumulate in the kidneys to a great extent because it could damage them.

Last year, the Central Clinic of Bad Berka, Germany reported on 56 patients treated with Lu-177-PSMA-I&T (see this link). 80% of treated patients had a PSA response and toxicity was minor. Heck et al.  at the Technical University of Munich reported on 19 metastatic castration-resistant patients who were treated with 7.4 GBq per cycle and up to 4 cycles.

• In 56%, PSA decreased by at least 30%
• In 33%, PSA decreased by at least 50%
• In 11%, PSA decreased by at least 90%
• Complete remission of metastases in 5%
• Metastases stayed stable in 63%
• Metastases progressed in 32%
• Performance status was stable or improved in 74%
• In those with bone pain, it was reduced partially or completely in 58%
• Mild (Grade 1 or 2) toxicities included dry mouth (37%), anemia (32%), and platelet loss (25%)
• There were no severe (Grade 3 or 4) toxicities.
• There was no kidney toxicity up to 40 GBq (see this link)

(Update 11/2018) Heck et al. updated the above with information on 100 patients. They were heavily pre-treated with a median of 3 pre-treatments. In fact, they were required to have had Zytiga or Xtandi, and at least one cycle of taxane chemo. They were all mCRPC and 35% had visceral metastases. They may have had up to 6 cycles of Lu-177-PSMA-617 (average was 3.2 cycles).

• In 38%, PSA decreased by at least 50%
• Median clinical progression-free survival was 4.1 months
• Median overall survival was 12.9 months
• Treatment-emergent hematologic grade 3/4 toxicities were anemia (9%), thrombocytopenia (4%), and neutropenia (6%)

A meta-analysis looked at the PSMA-I&T and PSMA-617 ligands in relation to the PSMA-J591 ligand. With a combined sample size of 369 patients across 10 studies, Calopedos et al. reported that:

• 68% of patients had some PSA decline
• 37% of patients had a PSA decline of at least 50%
• More patients had a PSA decline with the PSMA-I&T and PSMA-617 ligands, but there was a wide range of outcomes

These early indicators look good. Even if it just stabilizes performance status and mitigates bone pain in these end-stage patients, there is an important benefit. Of course, what we really want to see is evidence that it increases overall survival

While PSMA-I&T was developed to be a good ligand for imaging purposes as well as therapeutic purposes, a recent study found that, when used with Ga-68 (a positron emitter), PSMA-HBED-CC (also known as PSMA-11) was slightly better at detecting metastases (see this link). Another PSMA ligand, DCFPyL, that incorporates the positron emitter F18 into the ligand more tightly (avoiding chelation, which can easily be reversed), seems to be superior to the Ga-68-PSMA-HBED-CC PET tracer (see this link). Both DCFPyL PET and Ga-68-HBED-CC PET are in numerous clinical trials in the US and Canada. Lu-177 is a gamma emitter that can be seen by a gamma camera or via SPECT. However, it is usually used in conjunction with a positron-emitter in order to obtain a superior image.

Readers may wish to read these other articles on this subject:

Will Lutetium-177-anti-PSMA be the next Xofigo?
Lu-177-PSMA update
Lu-177-PSMA: another update
First in-human trial of Actinium-225-PSMA-617
Ac-225-PSMA-617 extends survival (update)
Ac-225-PSMA-617 (update)
I-131-MIP-135, a new radiopharmaceutical, in clinical trial at Memorial Sloan Kettering

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