Showing posts with label therapy comparison. Show all posts
Showing posts with label therapy comparison. Show all posts

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).





Saturday, February 22, 2020

ProtecT Randomized Clinical Trial: Patient outcomes by treatment received - active monitoring, prostatectomy, or radiation

In an earlier article (see this link), we looked at the only trial that randomized men with localized prostate cancer to either "active monitoring" (AM), radical prostatectomy (RP), or external beam radiation (EBRT). AM was less restrictive than today's active surveillance protocols (it included men who were not low risk) and it did not include mpMRI or follow-up biopsies. EBRT was lower dose than contemporary guidelines, included short-term ADT for everyone, and used a more toxic technique (3D-CRT) than IMRT prevalent today. RP was open and nerve-sparing. The earlier analysis categorized patients according to the treatment they were randomized to receive, rather than the treatment they actually received. They did this because it eliminates "selection bias" - patients switched to the treatment that they or their doctors believed would benefit them most. Now, the authors report patient outcomes according to the treatment they actually received.

1. Treatment choice/ oncological outcomes

In the first year, 78% of patients received the treatment they were randomly assigned. Higher risk men chose radical treatment rather than AM. Conversely, men with low-risk PC were less likely to opt for EBRT.

In the ten years of follow-up, there were only 17 prostate cancer deaths out of 1643 men randomized in the trial. The pooled, adjusted risks and the percent of the AM group that suffered each oncological outcome after 10 years of follow-up were:
  • 69% lower risk of prostate cancer death for radical therapy (RP or EBRT) vs AM 
    • 1.8% PC deaths among AM
  • 64% lower risk of metastases or death for radical therapy (RP or EBRT) vs AM 
    • 6.0% metastases or death among AM
  • 77% lower risk of progression for radical therapy (RP or EBRT) vs AM 
    • 24% progression among AM
  • 47% lower risk of salvage ADT for radical therapy (RP or EBRT) vs AM 
    • 8.8% salvage ADT among AM
  • No statistically significant differences between RP and EBRT
The inferior performance of their AM protocol was predictable (see this link - Section 3). Their AM protocol did not include mpMRI confirmation, biopsy follow-up, and allowed some higher-risk patients.


2. Urinary Adverse Outcomes

a. Incontinence

This was a big issue for RP, of course, but not for AM or EBRT. The percent using one or more pads per day is one commonly used measure. As one can see in the following table, incontinence was highest at the 6-month time point, but had gotten somewhat better by the end of the first year. 24% were incontinent by the end of two years, with little improvement from that point. Incontinence increased slowly in the AM group as they elected to have radical treatment.


Table 1. Incontinence: The percent who used one or more pads per day

Time point
AM
RP
EBRT
Baseline
0%
1%
0%
6 months
0%
55%
1%
1 year
1%
32%
2%
2 years
3%
24%
2%
3 years
3%
23%
2%
4 years
5%
20%
2%
5 years
5%
20%
2%
6 years
7%
21%
2%

b. Nocturia

The researchers examined the question of whether nighttime urination was more frequent after therapy. On this dimension, only EBRT had a clinically detectable effect, and it was only at the 6 month mark. After that, it returned quickly to AM levels. RP returned to baseline level.

Table 2. Nocturia - Twice or more per night

Time point
AM
RP
EBRT
Baseline
20%
22%
20%
6 months
24%
35%
65%
1 year
23%
26%
36%
2 years
28%
23%
32%
3 years
31%
25%
32%
4 years
33%
25%
33%
5 years
35%
23%
36%
6 years
38%
25%
34%

3. Rectal Adverse Outcomes

The researchers asked the trial participants whether they had blood in their stools half the time or more. There were no discernable effects of AM or RP. Blood in stools peaked at a low level (8%) of those who had EBRT.

Table 3. Blood in stools more than half the time

Time point
AM
RP
EBRT
Baseline
1%
1%
1%
6 months
1%
1%
4%
1 year
1%
0%
4%
2 years
0%
1%
7%
3 years
1%
1%
8%
4 years
1%
1%
8%
5 years
2%
1%
8%
6 years
1%
2%
6%

4. Sexual Adverse Outcomes

This is one of the few trials that asked men detailed questions about their sexual function at baseline and for 6 years thereafter. One of the key measures of sexual function is the ability to have erections firm enough for intercourse. At baseline, about two-thirds of these 62 year old men (range 50-69), some with other comorbidities like diabetes, cardiovascular disease, and smoking, had suitable erectile function. 

None of the questionnaires asked about perceptions of penile shrinkage in length and girth, climacturia (urination at orgasm), or Peyronie's (abnormal penile curvature), which are often symptoms that affect sexual function post-prostatectomy. Nor do they ask about how the loss of ejaculate has affected sex. That is a certainty with surgery, a near-certainty after radiation, and is not affected by AM. Their definition of erectile function includes the effect of any erectile function aids (e.g. ED meds, injections, pumps, or implants) they may have been using.

For those randomized to RP, erectile function was possible for 5% at 6 months (remember: they all had nerve-sparing surgery). It recovered somewhat to as much as 13% at 2 years but did not recover appreciably beyond that. At every time point, their erectile function was significantly worse than the other treatment cohorts.

For the AM cohort, erectile function declined by 6 months and continued to deteriorate thereafter as they aged and elected to have radical therapies, predominantly surgery. 

For the EBRT cohort, erectile function had dropped to a minimum value of 18% at 6 months. This may be largely attributable to the fact that all of the men in the EBRT cohort had 3-6 months of ADT. It is unknown how much, if any, of their testosterone came back after that and how long it took to recover. Erectile function snapped back a bit post-ADT, getting as high as 34% at 3 years. At 6 years, potency was twice ads high as those who had RP. Again, this was based on the 3D-CRT technology, and is below the rates usually seen for this age group with IMRT, brachytherapy, or SBRT.

Table 4. Erectile function - the percent who had erections firm enough for intercourse

Time point
AM
RP
EBRT
Baseline
68%
66%
63%
6 months
59%
5%
18%
1 year
60%
6%
34%
2 years
54%
13%
32%
3 years
49%
14%
34%
4 years
43%
15%
31%
5 years
40%
16%
28%
6 years
35%
15%
29%


Myths Exploded by this study:

Myth #1: The side effects end up about the same for surgery or radiation
Myth #2: With surgery, you get the side effects all at once and steadily recover; with radiation, the side effects come on steadily and may hit you many years later.
Myth #3: Over time, erectile function is about the same for surgery and radiation. 

Monday, November 26, 2018

Can surgery+radiation+ADT provide equal outcomes to brachy boost therapy +ADT in high risk men?

As we saw (see this link) among men with Gleason 9 or 10, brachy boost therapy (BBT: external beam radiation with a brachytherapy boost to the prostate) was shown to provide better oncological outcomes (10-year metastasis-free survival and 10-year prostate cancer-specific mortality (PCSM)) compared to surgery (RP) or external beam radiation (EBRT) alone. Some researchers argue that the comparison was unfair. In that study, 43% of the RP patients received adjuvant or salvage radiation, and virtually all of the BBT patients received 1 year of adjuvant ADT. What if ALL of the RP patients were to receive radiation and ADT?

Tilki et al. did a retrospective study to answer that question. They looked at two groups of Gleason 9/10 patients treated at two institutions between 1992 and 2013:

  • 559 men received RP+pelvic lymph node dissection (PLND) at the Martini-Klinik Cancer Center in Hamburg
    • 88 received adjuvant EBRT
    • 49 received adjuvant ADT
    • 50 received both (called MaxRP)
    • Median ADT duration - 8.6 months in 49 men with negative lymph nodes
    • Median ADT duration - 14.5 months in 39 men with positive lymph nodes
  • 80 men received BBT+ADT (called MaxRT) at the Chicago Prostate Center
    • Median ADT duration - 6 months
After 5.5 years of median follow-up for MaxRT and 4.8 years of median
follow-up for those receiving RP, they found that the risk of PCSM compared to MaxRT was:
  • 2.8 times greater for any RP (statistically significant)
  • 0.5 times less for RP+adjuvant EBRT (not statistically significant)
  • 3.2 times greater for RP+adjuvant ADT (statistically significant)
  • 1.3 times greater for MaxRP (not statistically significant)
The 5-year PCSM was:
  • 2% for MaxRT
  • 22% for any RP (significantly higher than MaxRT)
  • 4% for RP+adjuvant EBRT (not significantly different from MaxRT)
  • 27% for RP+adjuvant ADT (significantly higher than MaxRT)
  • 10% for MaxRP (not significantly different from MaxRT)
They computed a 76% chance ("plausibility index") that the PCSM was plausibly the same for MaxRT vs. MaxRP.

Kishan et al. supplied numbers from his study that are more directly comparable. They are shown in the table below.

Study
Tilki
Kishan
Sample size
BBT: 80
RP+EBRT: 88
RP+ADT: 49
RP+EBRT+ADT: 50
BBT: 436
RP+EBRT: 272
RP+ADT: 175
ADT duration (median)
BBT: 6 months
RP (N1): 14.5 mos.
RP (N0): 8.6 mos.
BBT: 12 months
Among RP,% N1
44%
17%
5-year % PCSM
RP (any): 22%
BBT: 2%
RP (any): 12%
BBT: 3%
Adjusted PCSM Hazard Ratio compared to BBT:
RP+ADT: 3.2
RP+EBRT: 0.5 (not sig.)
RP+ADT: 3.2
RP+EBRT: 2.0


We see that the two studies are really not comparable in some respects. The Kishan study was much larger, and was done among many of the top institutions. The Hamburg patients had a much higher percent of positive lymph nodes, and their mortality was twice as high as in the Kishan study. The Chicago patients only got half as much ADT vs. the Kishan study. Importantly, the Kishan study found that RP+EBRT had PCSM that was twice as high as BBT, while the Tilki study showed no statistically significant difference.

Another important aspect was not reported in either study - the toxicity of treatment. We know that surgery plus radiation has worse urinary and sexual side effects compared to surgery alone.BBT carries risk of higher late-term urinary side effects compared to EBRT alone.

Until we have a randomized clinical trial of BBT vs MaxRP, we will never have certainty, but for now, the Kishan study better reflects expected outcomes of these therapies at top institutions.