Showing posts with label SBRT. Show all posts
Showing posts with label SBRT. Show all posts

Wednesday, March 17, 2021

Whole gland TULSA-PRO 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.

It is hard to see why anyone would choose TULSA-PRO over SBRT. While focal ablation may incur less toxicity, the local recurrence rate will be higher. This trial suggests that  TULSA-PRO is inferior, although only a direct randomized comparison could prove that.

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



Sunday, January 24, 2021

SBRT for High-Risk Patients

As we have seen, SBRT is a preferred therapy for low and intermediate-risk patients (see this link). It is effective, safe, convenient, and relatively inexpensive. However, its use for high-risk patients remains controversial.

Amar Kishan has accumulated data from 8 institutions that have used SBRT for 344 high-risk patients. They were treated as follows:

  • They received from 35 Gy-40 Gy in 5 treatments (7-8 Gy per treatment)
  • 72% received adjuvant ADT for a median of 9 months
  • 19% received elective nodal radiation

After a median follow-up of 49.5 months:

  • 4-year biochemical recurrence-free survival  (bRFS)was 82%
    • Higher dose, longer ADT, and nodal radiation were associated with better bRFS
  • 4-year metastasis-free survival was 89%
  • Late grade 3 GU toxicity was 2.3%
  • Late grade 3 GI toxicity was 0.9%
    • Toxicity was associated with dose and ADT use

Although the results of different prospective trials aren't comparable, the following table gives an idea of 4-6 year outcomes of prospective trials of high-risk patients using various therapies.

 

Follow-up

bRFS

BED

ADT (median)

Late GU Toxicity Grade ≥3

SBRT (1)

4 yrs

82%

198-253 Gy

9 mos.

2.3%

Surgery+SRT (2)

5 yrs

78%

154 Gy

6 mos.

8% (3)

HDR-BT (4)

5 yrs

91%

227-252 Gy

6.3 mos.

3-16%

LDR- Brachy Boost (5)

5 yrs

86%

227 Gy

12 mos.

19%

HDR-Brachy Boost (6)

6 yrs

88%

267 Gy

12 mos.

2.5%

IMRT (7)

5 yrs

88%

174 Gy

28 mos.

2.5%


SBRT = stereotactic body radiation therapy,. External beam radiation (EBRT) concentrated in 5 treatments
bRFS= biochemical (PSA) recurrence-free survival
BED= biologically effective dose (comparable effectiveness)
ADT= androgen deprivation therapy used for a limited time to improve outcomes
late GU toxicity ≥3 = serious urinary side effects requiring intervention, occurring more than 3 months after therapy
HDR-BT = high dose rate brachytherapy (temporary implants)
LDR-BT = low dose rate brachytherapy (permanent implants/seeds)
Brachy Boost therapy - External beam radiotherapy (EBRT) with a boost of radiation to the prostate using brachytherapy 
IMRT = intensity-modulated radiation therapy, usually given in about 40 treatments

(1) https://www.redjournal.org/article/S0360-3016(21)00068-7/pdf
(2) https://riskcalc.org/ProstateCancerAfterRadicalProstatectomyNew/ with GS 8
(3) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00111-X/fulltext
(4) https://www.redjournal.org/article/S0360-3016(11)00552-9/abstract
(5) https://www.redjournal.org/article/S0360-3016(16)33484-8/abstract
(6) https://www.thegreenjournal.com/article/S0167-8140(18)30238-X/fulltext
(7) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70045-8/fulltext

As we've seen (see this link), brachy boost therapy is the gold standard for long-term recurrence-free survival. At about 5 years, however, all therapies seem to be about equally effective, with biochemical recurrence-free survival in the range of 78-91%. However, they differ markedly in the incidence of serious late-term urinary side effects. For LDR Brachy Boost therapy, the risk of urinary retention is high, while the risk of incontinence and urinary retention is elevated among patients having salvage radiation (SRT). External beam monotherapy, using either IMRT or SBRT, had a low risk of serious late-term urinary side effects (and almost no risk of serious rectal side effects).

IMRT, as a primary therapy for high-risk patients, requires long-term use of ADT to be effective. The DART RADAR trial showed that for high-risk patients, 6 months of adjuvant ADT wasn't nearly enough. Nabid suggests that 18 months of adjuvant ADT may be optimal when paired with IMRT. SBRT seems to be equally effective with less adjuvant ADT, but the optimal duration is yet to be determined.

The question that will only be resolved with longer follow-up is whether the recurrence rates are stable after 4 years, or whether they will deteriorate with longer follow-up. In the ASCENDE-RT trial of brachy boost therapy vs external beam radiation only, biochemical recurrence rates were similar after 5 years. Recurrence increased at a rate of 5% per year among those treated with EBRT alone, but only at a rate of 1% per year if they got the brachy boost. There was similar stability of outcomes when HDR brachytherapy was used. Recurrence after salvage radiation increased from 22% at 5 years to 30% at 10 years. There is every reason to believe that SBRT, which uses biologically effective doses (BED) of radiation similar to brachy boost therapy, will follow a stable recurrence pattern over time, but that remains to be shown.

Ensuring the safety of patients is critical, and high-risk patients are usually treated with wider margins that can affect toxicity. As we saw, SBRT there are many factors that must be considered when giving radiation this intense (see this link).

The first randomized trial (see this link) of radiation delivered in 6 treatments compared to 39 treatments to intermediate to high-risk patients proved that the cancer control and toxicity were similar. Another randomized trial (PACE-B) has already shown that the toxicity is lower with SBRT. An ongoing arm of that trial (PACE-C) is focusing on high-risk patients.

NCCN has included SBRT as a reasonable standard-of-care option for high-risk patients (Table 1 Principles of Radiation Therapy PROS-E 3 of 5 in NCCN Physicians Guidelines 3.2020). Due to the pandemic, an international panel of radiation oncologists is recommending that high-risk patients consider its use (see this link).





Tuesday, September 17, 2019

SABR to oligometastases slows progression via immune response

Stereotactic Ablative Body Radiation (SABR, or sometimes, SBRT) significantly slowed metastatic progression in men with 3 or fewer metastases (oligometastatic). SABR is a form of concentrated radiation accomplished in 1-5 treatments.

The ORIOLE trial has been previously described in detail here. To recap, it was a small (Phase 2) randomized trial with 36 men treated with SABR to bone scan/CT-detected oligometastases. There were 18 men in the untreated control group. The men were followed for 6 months to see if there was any progression of their cancer. Progression was defined as either PSA progression or new metastases detected on bone scan/CT or physical symptoms of decline (e.g., pain). Of course, with only 6 months of follow-up, most of the detected progression was PSA progression. Phuoc Tran, the lead investigator of the ORIOLE trial, reported the 6-month results here:
  • Progression-free survival (PFS) was 81% in the SABR group vs 39% in the control group.
  • Median PFS was not yet reached in the SABR group vs 5.8 months in the control group.
  • The time to progression was increased by 70% by the treatment.
  • Progression has not been reached among those treated patients followed for over a year.
Although patients were only treated for metastases discovered on a bone scan/CT, they were also given a PSMA-based PET scan (DCFPyL). Those in whom no additional metastases were discovered by the PET scan fared better:
  • PFS was 84% in the fully treated group vs 36% in those with undiscovered metastases.
  • Median PFS was not reached in the fully-treated group vs 11.8 months in those with undiscovered metastases.
  • Distant metastasis-free survival (i.e., metastases distant from the ones that were treated) was 29 months in the fully-treated group vs 6 months in those with undiscovered metastases.
PFS in men in whom there were any untreated metastases was not improved compared to untreated men. This seems to be an all-or-nothing sort of thing.

SBRT has been found in lab studies to elicit a strong immune response. It releases cancer antigens into the bloodstream that are detected by T-cells, which become activated to find more cancer. That T cell response to radiation is thought to contribute to its effectiveness (called "the abscopal effect"). The investigators tracked the T cell response and found a significant response in the SABR-treated men.

Progression-free survival when most of the progression is PSA progression is not the endpoint we need to evaluate this therapy. SABR "treats" PSA. "Treating PSA" would occur if the radiation only provides excellent local control, while not necessarily delaying progression elsewhere. PSA is secreted in proportion to the size of the tumors, so treating only the tumors will do nothing to stop the micrometastases that are elsewhere. However, the strong T-cell response found by this study suggests that there may be a true delay in progression and not only a delay in PSA. Also, the fact that distant metastases were delayed by almost 2 years among those who had all of their PSMA-detected metastases irradiated, suggests a true response.

This is an important first step toward discovering whether oligometastasis-directed therapy provides a benefit, and how it works. It does not yet provide the answer to whether there is a survival benefit to such therapy. It also does not answer the question of whether ADT can be delayed when radiation has been given. There are several, larger clinical trials that will answer those questions more definitively. Meanwhile, the patient with rising PSA after prostate therapy should consider:
  1. A PSMA-based PET scan (available in some clinical trials, and probably widely available within a year).
  2. Talking to a radiation oncologist about SABR treatment of metastases if all discovered metastases are in places where it is entirely safe to treat them
  3. Not forgoing ADT adjuvant to SABR treatment until there is more proof.

Saturday, February 16, 2019

SBRT has non-inferior acute and late-term toxicity vs IMRT in two randomized clinical trials

In October 2018, the American Society of Radiation Oncologists (ASTRO) strongly endorsed moderately hypofractionated IMRT (20/28 treatments) for primary radiation treatment (see this link). Since then, there has been another publication of a randomized clinical trial with ten years of follow-up (see this link).

The advantages for the patient are large: fewer visits than the conventional 38-44 treatments with a concomitant reduction in costs. Because there is now convincing proof that this can be accomplished without an increase in side effects and without loss of oncological effectiveness, there is no reason why any patient would suffer through the conventional regimen. The remaining question is whether the number of treatments (or fractions) can be reduced even further to only about 4 or 5. This kind of extreme hypofractionation is called stereotactic body radiation therapy or SBRT. This requires proof.

We have seen the results of a Scandinavian randomized clinical trial (RCT) that found that urinary, rectal, and sexual side effects were not inferior with extreme hypofractionation (see this link), and the oncological outcomes were about the same too (see this link).

Now two more RCTs have shown that the toxicity of SBRT is no worse than and possibly better than moderately hypofractionated or conventionally fractionated IMRT.

Van As et al. reported the acute toxicity results of the PACE-B RCT in the UK at the Genitourinary Conference of ASCO. 844 men with favorable risk prostate cancer were randomized to get SBRT (414 men) or conventionally fractionated/moderately hypofractionated  IMRT - "CFMHRT" (430 men). The qualifications were:

  • localized, favorable risk prostate cancer (Gleason score ≤ 3+4, Stage T1 or T2, PSA ≤ 20 ng/ml)
  • unsuitable for surgery or preferring radiation

The two groups were similar. The treatments were:

  • SBRT: 36.25 Gy in 5 fractions over 1-2 weeks
  • CFMHRT: 78 Gy in 39 fractions (conventional) or 62 Gy in 20 fractions (moderately hypofractionated)
  • ADT was not permitted

At 12 weeks post treatment, acute grade 2 or higher toxicity was:

  • rectal: 10% for SBRT vs 12% for CFMHRT - difference was not statistically significant
  • urinary: 23% for SBRT vs 27% for CFMRT - difference was not statistically significant

Poon et al. reported the one year late-term toxicity results of a RCT in Hong Kong. 64 low- and intermediate-risk patients were randomized to get SBRT (31 patients) or conventionally fractionated IMRT - "CFIMRT" (33 patients). The qualifications were: Stage T1 or T2, Gleason score ≤ 7, and PSA < 20 ng/ml.

The treatments were:

  • SBRT: 36.25 Gy in 5 fractions over 2 weeks
  • IMRT: 76 Gy in 38 fractions
  • Intermediate risk patients could optionally have ADT before their radiation.

at 1 year post treatment:

  • one grade 3 (serious) urinary side effect was reported in each arm
  • rectal grade 1 (mild) or higher: 64% for SBRT vs 84% for CFIMRT - significantly different
  • urinary grade 1 (mild) or higher: 93% for SBRT vs 100% for CFIMRT - not significantly different


It is too early to assess if there are any differences in oncological outcomes in these two RCTs.




Monday, January 7, 2019

SBRT: Optimal Dose

While excellent outcomes of stereotactic body radiation therapy (SBRT) have been reported since it was first used for prostate cancer in 2003, the delivered doses have ranged from 35 Gy in 5 treatments to 40 Gy in 5 treatments. We saw in a University of Texas Southwest (UTSW) study (see this link) that toxicity escalates when doses are greater than 45 Gy.

Memorial Sloan Kettering designed a clinical trial (described here) among low and intermediate-risk men. They started with about 35 men treated at 32.5 Gy and checked for dose-limiting toxicity. When most reached 6 months of follow-up, and fewer than 10% had dose-limiting toxicity, they increased the dose to the next group of 35 men by 2.5 Gy in 5 treatments. In all, they had 136 patients who were followed up for 5.9 yrs, 5.4 yrs, 4.1 yrs and 3.5 yrs with doses of 32.5 Gy, 35 Gy, and 37.5 Gy and 40 Gy, respectively.

Their toxicity and oncological outcomes are reported here and shown in the table below:



Dose delivered in 5 treatments

32.5 Gy
35.0 Gy
37.5 Gy
40.0 Gy
Acute toxicity




Urinary – grade 2
16.7%
22.9%
8.3%
17.1%
Rectal – grade 2
0%
2.9%
2.8%
11.4%
Late-term toxicity




Urinary – grade 2
23.3%
25.7%
27.8%
31.4% (1 grade 3 stricture)
Rectal – grade 2
0%
0%
0%
0%
Oncological outcomes




5-year PSA failure
15%
6%
0%
0%
2-year positive biopsy
47.6%
19.2%
16.7%
7.7%

Other than the one urinary stricture, there were no acute or late-term grade 3 (serious) toxicities.

Because follow-up decreased with increasing dose, it is unclear whether the zero biochemical failure rates for doses of 37.5 Gy and 40 Gy will be sustained, but in other studies, almost all SBRT failures had occurred within 5 years. The positive biopsy rates will probably continue to decline with longer follow-up because the non-viable cancer cells can take up to 5 years to clear out. Clearly, 32.5 Gy is too low because of its unacceptable oncological results.

A dose of 40 Gy in 5 treatments has very acceptable toxicity and excellent cancer control. It would be reasonable to use doses as low as 37.5 Gy in patients with insignificant amounts of low grade cancer (who would usually be excellent candidates for active surveillance). Based on the UTSW study, it would be reasonable to escalate the dose as high as 45 Gy in patients judged to have radioresistant cancers.