Wednesday, March 17, 2021

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

Br√ľndl 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



13 comments:

  1. Not sure that I follow the second line in your chart. Shouldn't the biological recurrence-free survival be 65 percent for TULSA-PRO?

    - ASAdvocate

    ReplyDelete
    Replies
    1. No. It is BIOCHEMICAL recurrence-free survival (i.e., PSA), not "biological." PSA didn't increase, but the cancer remained.

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    2. Allen -

      will you be posting this on Healthunlocked?

      Delete
    3. I posted a link there yesterday.

      Delete
  2. Thanks, Allen. This is a sobering read. All of us on AS appreciate your bringing these studies to a wide audience.

    ReplyDelete
  3. One wonders how many of the GL3+3 men could have been managed with active surveillance instead. The TULSA Pro experience correlates with my experience using MRgFUS to treat uterine fibroids. I found amazing short term symptom relief in my patients who had the fibroid tumor heated to 65C. Unfortunately, the tumors only shrank about 30% in size by 6 months and many began to regrow.
    Is there a similar analysis available for FLA and Cryo, which I expect might indicate similar findings.

    ReplyDelete
    Replies
    1. Most were high volume GS3+3 or GS3+4, but still I agree with you that most could have been on AS. I don't think that whole gland FLA is used, but focal results are similarly poor: https://www.auajournals.org/doi/pdf/10.1097/JU.0000000000000860.01

      Delete
  4. The writer is biased toward radiation. 18% urinary toxicity for SBRt isn’t trivial compared to 0%. Who wants to wear a diaper forever?

    ReplyDelete
    Replies
    1. None of that is incontinence. It is almost entirely Grade 2 (annoying) irritative symptoms (i.e., frequency, urgency, retention) that are temporary and are easily treated with short-term use an alpha blocker (like Flomax). It is a price most of us would gladly pay for curative therapy.

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  5. Now that we have PSMA PET scans to better identify those who have disease spread (prior to treatment) and we know that calcifications can cause issues with HIFU or TULSA, it might be interesting to see new data where those being treated by HIFU or TULSA might be a better fit for those treatments. Additionally, newer TULSA treatment test results show that cranking up the temp by about 2 degrees c really improve outcomes in intermediate patients

    ReplyDelete
    Replies
    1. Behfar Ehdaie tried to "crank up" the heat. He used MRI to see and treat with unprecedented detail.The results were dismal: 20% still had cancer in the ablation zone, 12% Grade Group 2 or higher; 60% still had cancer in the prostate, 40% Grade Group 2 or higher. And among men with good erectile function at baseline, erectile function dropped by 40% https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00251-0/fulltext
      Whether calcifications or some other reason cause the high failure rates, it is incumbent upon researchers to further investigate the physical and biochemical reasons before continuing. This, they have so far failed to do.

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  6. HIFU (High Intensity Focused Ultrasound using high frequency soundwaves to ablate tumors) has a range of success from 61% to 95% or 24%, 37% and 43% depending who you read.

    A study was published online in 2022: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877347/#:~:text=In%20our%20study%2C%20HIFU%2DFT,provided%20significantly%20better%20functional%20outcomes.

    The authors conclusions:
    "In our study, HIFU-FT was associated with a higher rate of treatment failure than laparoscopic radical prostatectomy. However, it provided significantly better functional outcomes. Based on the presented results, we believe that HIFU-FT remains a viable treatment option in selected patients motivated to preserve their erectile function and urinary continence yet accepting a slightly increased risk of compromised oncologic results."
    "...it provided significantly better functional outcomes..." suggests good Quality of Life. Like the authors of this study, I would like to see "data from randomized controlled trials comparing its oncological efficacy with radical treatment." And if I could be pointed to a study comparing oncological results of both HIFU and radiation in two groups of men. That would be helpful.

    ReplyDelete
    Replies
    1. 100% It fails to do job #1 - get rid of the cancer. I've asked for randomized trials. The response I get is "patients don't want to be randomized." I think that's because patients are not informed about the high failure rates.

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