Whole gland TULSA-PRO and HIFU outcomes: Is it time to give up on thermal ablation for prostate cancer?

 We have seen that there are many unanswered questions about focal thermal ablation (see this link), among them are:

1. Is Index Tumor Theory valid?
2. Can foci of cancer be precisely targeted using current imaging methods?
3. Does thermal ablation completely ablate the cancer in the ablation zone?
4. Will the Heat Sink Effect and biochemical protective mechanisms (e.g., heat shock proteins) always cause sub-lethal killing?
5. Is toxicity and damage to organs at risk any better than radical (whole gland) radiation?
6. How do the high "re-do" rates affect toxicity and costs?
7. How do we track success?
8. What are the best salvage therapies?
9. Can it extend the time on active surveillance?
10. What are the intra-operative risks?
11. What is the learning curve like for therapists?
12. Is it worth the cost?

Laurence Klotz et al. conducted a clinical trial of a new kind of high-intensity focused ultrasound (HIFU). He studied whole-gland ablation because current FDA rules only permit ablation for removal of prostate tissue (like a TURP), but not for treatment of prostate cancer. In fact, the FDA specifically rejected HIFU for the treatment of prostate cancer. 

TULSA-PRO utilizes a thermal feedback loop to assure that tissue temperature reaches the desired heating. It is done "in-bore" in an MRI by a team consisting of a urologist and an interventional radiologist, and an anesthesiologist (full anesthesia was required). It was hoped that the MRI precision and assured tissue heating (to 55°C) would afford higher cancer-killing with less toxicity.

115 patients were carefully selected:

• 15% were low volume GS 3+3 (cancer in ≤2 cores, <50% in any core)
• 23% were high-volume GS 3+3
• 60% were GS 3+4
• 3% were GS> 3+4
• 94% were T1c or T2a
• Median PSA=6.3
• 67% were intermediate risk (predominantly favorable)
• 33% were low-risk
• Median prostate volume was 40 cc.

The operative procedure involved:

• prophylactic antibiotics
• general anesthesia
• cystoscopy
• transurethral US heating wand
• pelvic tissue at apex avoided to avoid incontinence
• endorectal cooling device
• 243 minutes (4 hours), start to finish
• suprapubic catheter (17 days)

Safety Outcomes/ Adverse Events:

Physician-reported outcomes:

• Acute (immediate) Grade 2:
• erectile dysfunction (29%)
• UTI (25%)
• bladder spasm (10%)
• painful urination (10%)
• urinary retension (8%)
• pain (7%)
• incontinence (6%)
• epidydimitis (5%)
• Acute (immediate) Grade 3 (severe, requiring intervention):
• infection (4%)
• urethral stricture (2%)
• urinary retention (1.7%)
• urethral calculus and pain (1%)
• urinoma (1%)
• long-lasting Grade 2 adverse events:
• erectile dysfunction (23%)
• incontinence (3%)
• recurrent infections (2%)

Patient-reported outcomes at 12 months vs baseline on EPIC questionnaire (% reporting moderate decline/ % reporting moderate gain):

• Sexual domain: 32%/ 1%
• ED on IIEF-15 questionnaire: 35%/6%
• 75% of previously potent men returned to erections sufficient for penetration with only ED meds.
• Urinary incontinence:14%/7%
• Urinary irritation/obstruction: 8%/5%
• Bowel domain: 5%/2%

Oncologic Outcomes (at 12 months):

• 35% had residual cancer at biopsy
• 24% among low volume GS 6
• 38% among high volume GS 6
• 37% among GS 3+4
• Median PSA reduced to 0.5 ng/ml
• Median prostate volume reduced to 2.8 cc
• PIRADS ≥3: 30%

There is little 12-month data available for other therapies, but recurrence rates almost always increase with time. There was a 2-year study of SBRT at Georgetown that may be roughly comparable:

	TULSA-PRO (1 year) 115 patients	SBRT (2 years) 100 patients
Risk category Low-risk Intermediate-risk High-risk	33% 67%	37% 55%  8%
Biochemical recurrence-free survival	100%	99% (1 local recurrence in a high-risk patient)
Biopsy-proven local recurrence	35%	1% estimated in the high-risk patient
Nadir PSA	0.5 ng/ml	0.5 ng/ml
Acute urinary toxicity (grade 3)	8%	0%
Acute rectal toxicity (grade 3)	0%	0%
Late-term urinary toxicity (grade 2+)	5%	18%  (1% Grade 3)
Late-term rectal toxicity (grade 2+)	0%	0%
Potency preservation among previously potent men	75%	79%

Full-gland TULSA-PRO seems to treat PSA without eradicating the cancer (see this link). In about a third of favorable-risk patients, the cancer remained viable in spite of the thermal ablation. We see that compared to whole-gland SBRT, it is less curative, Severe (requiring intervention) acute urinary toxicity is higher with TULSA-PRO, although late-term Grade 2 urinary toxicity is lower (not severe for either therapy). Rectal toxicity is not an issue for either therapy. Potency preservation is good and about equal for both.

15-year study suggests long-term inferiority

Bründl et al. reported 15-year oncological outcomes of 674 patients treated with whole-gland HIFU at one university hospital in Regensberg, Germany. Notably, overall survival and prostate cancer-specific survival were high in all localized risk categories. However, comparing 15-year prostate cancer-specific survival to similar risk men who have undergone prostatectomy at Memorial Sloan Kettering, we see the survival is relatively poor:

15-yr Prostate Cancer-Specific Survival

Risk Group	HIFU	RP*
Low Risk	95%	99%
Intermediate Risk	89%	98%
High Risk	65%	88%

* from the MSK pre-prostatectomy nomogram for a 62 yo man. For low-risk, he had PSA=5, GS 3+3, stage T1c, and 25% positive cores; For intermediate-risk, he had PSA=15, GS 4+3, stage T2c, and 50% positive cores; for high risk, he had PSA=25, GS 4+5, stage T3a and 100% positive cores.

The longest follow-up study there is for SBRT is 12 years. For SBRT, Alan Katz reported rates of "local control" on SBRT - the percent of patients who had recurrences only in the prostate. These could all theoretically be cured with a re-do of SBRT, focal brachytherapy or focal ablation. We can look at long-term local control from SBRT next to the long-term reported rates of salvage therapy after whole-gland HIFU (either re-do of HIFU or other salvage). HIFU does not compare well:

% patients who do not require salvage treatment

Risk Group	HIFU	SBRT
Low Risk	77%	97%
Intermediate Risk	52%	92%
High Risk	28%	88%

It is hard to see why anyone would choose HIFU or TULSA-PRO over SBRT. While focal ablation may incur less toxicity, the local recurrence rate will be much higher. These trials suggest that  HIFU and TULSA-PRO are inferior, although only a direct randomized comparison could prove that definitively.

For an article discussing the use of focal ablation as an active surveillance "extender," see:

What should focal therapy be compared to and how does it compare?

For an article discussing salvage focal ablation after the failure of radiation therapy, see:

Focal salvage ablation for radio-recurrent prostate cancer