Lower salvage radiation dose - are outcomes the same?

A large randomized clinical trial, SAKK 09/10, found that a salvage radiation dose of 64 Gy over 32 treatments had equivalent biochemical outcomes compared to 70 Gy over 35 treatments.

They treated 350 patients from 2011 to 2014 at 28 hospitals in Germany, Switzerland, and Belgium. They were treated with either 3D-CRT (44%) or more modern radiation techniques. None had positive lymph nodes. Key patient characteristics were as follows:

• Biochemically recurrent after prostatectomy (median PSA= 0.3 ng/ml)
• Positive margins in 45%
• Gleason score ≥ 8 in 18%
• No detectable tumors

After 6.2 years of follow-up, outcomes were as follows:

• Freedom from biochemical progression (FFBP) was enjoyed by 65% of those who got 64 Gy vs 73% of the 70 Gy group. This difference is not statistically different (p=0.11).
• Local recurrences (only) occurred in 9% of the 64 Gy group vs 2% of the 70 Gy group. This difference is statistically significant (p= 0.005)
• Regional recurrences (only) occurred in 11% of the 64 Gy group vs 17% of the 70 Gy group. This difference is not statistically significant (p= 0.11)
• Distant recurrences (any) occurred in 15% of the 64 Gy group vs 15% of the 70 Gy group.
• In an earlier report, acute urinary toxicity of Grade 2 or greater occurred in 14% of the 64 Gy group vs 18% of the 70 Gy group (not different)
• In an earlier report, acute rectal toxicity of Grade 2 or greater occurred in 17% of the 64 Gy group vs 18% of the 70 Gy group (not different)
• Late urinary toxicity of Grade 2 or greater occurred in 29% of the 64 Gy group vs 30% of the 70 Gy group (not different)
• Late rectal toxicity of Grade 2 or greater occurred in 12% of the 64 Gy group vs 22% of the 70 Gy group (different)
• Patient-reported outcomes were not different between the two dose regimens.

Oncological Outcomes

The stated purpose of SAKK 09/10 was to detect a difference in 6-year FFBP, and they detected no difference. But is that enough to change practice? The ICECAP working group cautions  that 5-year metastasis-free survival, but not biochemical recurrence-free survival, is a good surrogate endpoint when overall survival would take too long to obtain in trials of primary therapy for localized prostate cancer. For trials of salvage therapy of recurrent prostate cancer after prostatectomy, some early analysis suggests that the 5-year occurence of distant metastases may be a good surrogate endpoint. 6-year FFBP used in this trial is probably not a good surrogate endpoint.

Focusing our attention on the actual cancer progression instead of just PSA progression, we see that the higher dose did significantly better at preventing local progression of the cancer. If the trial were to run 15 years, we might see a very meaningful difference between the curative powers of the two dose regimens. Furthermore, as shown in the SPPORT trial, salvage treatment of pelvic lymph nodes, even when none is detectable, may slow progression or possibly cure some patients with regional micrometastatic progression. 

There may be other ways to improve outcomes:

• Using the expanded prostate bed delineation guidelines may improve local control.
• As PSMA PET/CT becomes more widely available, it will be possible to detect more loco-regional cancer for boost doses, and eliminate salvage treatment from patients who already have small distant metastases (see this link). 
• The use of genomic tests, like Decipher Genomic Classifier (GC), may aid in selecting patients in whom higher doses are needed. In a subset analysis, among Decipher "high GC-risk" patients, FFBF was 51% for 70 Gy vs 39% for 64 Gy patients; among Decipher "low GC-risk" patients, FFBF was 75% for 70 Gy vs 69% for 64 Gy patients (update) FFBF was 45% for GC-high patients vs 71% for GC-low patients. 
• There is a clinical trial at UCLA that will determine whether raising the biologically effective dose (BED) using SBRT (34 Gy/ 5 fractions) gives good outcomes compared to historical controls. The BED is equivalent to 85 Gy if given in fractions of 1.8 Gy.
• There is a clinical trial in France that will determine whether adjuvant hormone therapy intensification with Erleada improves results.
• Keeping in mind that very few patients in this trial had Gleason scores of 8-10, and none had detectable gross tumors at or near the prostate, those patients may still be good candidates for dose intensification (as well as adjuvant ADT).

Toxicity Outcomes

If there is no cost to the patient in terms of increased toxicity, there is no reason not to increase the dose. The patients were unable to detect a difference in urinary, rectal, or sexual outcomes. There was a difference in physician-reported late-term rectal toxicity that deserves further attention.

Compared to acute urinary toxicity, late-term urinary toxicity is about twice as bad in both dosing regimens, although the ratings are not different between regimens. Compared to acute rectal toxicity, late-term rectal toxicity was 29% lower for the 64 Gy dose group, but marginally higher for the 70 Gy dose group. The authors believe that rectal dose constraints could be tightened with IMRT.

For comparison, MSK reported that using 70 Gy as a salvage dose, late-term urinary toxicity (Grade≥2) was 17% (vs 30% in this trial) and late-term rectal toxicity (Grade≥2) was 5% (vs 22% in this trial). They also reported that IMRT improved rectal toxicity over 3D-CRT, while no difference was observed in this trial.

The reason for these atypical results is mysterious, although physician-reported toxicities are notoriously unreliable.

So, lacking more reliable endpoints and considering that patients did not notice any difference in their quality of life based on dose intensification, the decision on what dose to use is best based on a discussion with the radiation oncologist.

(update 04/22/2022) Beck et al. report that adherence to treatment guidelines was poor in the SAKK 09/10 trial. This may explain the mysterious toxicity results as well as being responsible for worse freedom from biochemical progression.

Brief, intense radiation and hormone therapy for very high risk prostate cancer

(updated)

As we've seen, brachy boost therapy seems to have the best oncological results for men with very high-risk prostate cancer. But brachy boost therapy entails 20-25 external beam radiation treatments plus the invasive placement of radioactive seeds or needles plus at least 18 months of testosterone suppression. While the oncological results are excellent, with about 80% cure rates, there is significant risk of serious late-term urinary retention. In some men, testosterone never fully recovers.

McBride et al. reported the early results of the AASUR trial. The goal of the trial was to find a treatment with equivalent oncological outcomes, but one that is easier on the patient, with less risk of long-term toxicity. They recruited 64 patients at 4 top institutions (Memorial Sloan Kettering, Johns Hopkins, University of Michigan, and Thomas Jefferson University). All patients were "very high risk," defined as:

• any Gleason score (GS) 9 or 10, or
• 4 or more cores of GS 8, or
• 2 high-risk features (stage T3/4, GS 8, or PSA>20)
• No metastases (N0, M0)

Patients were treated with:

• SBRT (7.5-8.0 Gy x 5 treatments)
• 6 months of Lupron, Erleada, and Zytiga

After 30 months of follow-up:

• 90% were free of biochemical failure
• Median PSA at the last follow-up was 0.1
• PSA remained undetectable in 40%
• Testosterone rose to non-castrate levels at a median of 6.5 months after hormone therapy ended, and almost all rose to >150 ng/dl
• 23% experienced transient serious toxicities, mostly hypertension
• Quality of life scores at 1 year held for urinary and rectal domains but declined in sexual and hormone domains.

How do these results compare to other trials of radiation+ADT in high-risk patients?

Lin et al. used whole pelvic IMRT with an SBRT boost to the prostate and 2 years of ADT in 41 high- and very high-risk patients. With 4 years of follow-up, they reported 92% biochemical recurrence-free survival (bRFS).

Hoskin et al. used high dose rate brachytherapy as a monotherapy in 86 high-risk patients. Most (80%) had adjuvant ADT for a median of 6.3 months (range 1-40 months). With 4 years of follow-up, they report 87% biochemical recurrence-free survival (bRFS) among high-risk patients.

Zapatero et al. reported the results of the DART 01.03 GICOR trial of escalated dose IMRT with either short-term (4 months) or long-term (28 months) ADT. There were 185 high-risk patients with about half getting each ADT protocol. About a quarter received simultaneous radiation of their pelvic lymph nodes. With 5 years of follow-up, they report 76% bRFS among high-risk patients who got short-term ADT and 88% bRFS among high-risk patients who got long-term ADT.

(Update) Murthy et al. reported results of a trial where 224 men with ≥ 20% risk of pelvic lymph node metastases were screened with PSMA PET scans and were randomized to get whole pelvic radiation with a boost to the prostate or prostate-only radiation. They all received 2 years of adjuvant ADT. With 5 years of follow-up, they reported 95% bRFS. 

This table summarizes these trials:

	AASUR	SBRT boost (Lin)	HDR-BT (Hoskin)	IMRT DART  GICOR	IMRT DART  GICOR	IMRT POP-RT
follow-up	2.5 yrs	4 yrs	4 yrs	5 yrs	5 yrs	5 yrs
Radiation	SBRT	IMRT+ SBRT boost	HDR-BT  monotherapy	IMRT  (dose escalated)	IMRT  (dose escalated)	WP:50Gy/25fx boost:18Gy/25fx
Coverage  area over  prostate	SV	Whole pelvic	±SV (if MRI+)	• SV • 27%  whole pelvic	• SV • 19%  whole pelvic	Whole pelvic
Adjuvant  hormone  therapy	ADT+Zytiga+Erleada	93% ADT	80% ADT	ADT	ADT	ADT
Duration of  hormone  therapy	6 mos.	2 yrs	6.3 mos.	4 mos.	28 mos.	2 yrs
Risk	VHR	78% HR 22% VHR	HR	HR	HR	≥20% LN risk
bRFS	89%	92%	87%	76%	88%	95%

HR=high risk VHR=very high risk SV=seminal vesicles bRFS=biochemical recurrence-free survival: PSA stayed lower than nadir+2.0 ng/ml

2.5 years of follow-up is too early to draw valid conclusions. We see that most of the trials had higher bRFS even with much longer follow-up; however, only AASUR recruited very high-risk patients exclusively. ICECAP has shown that only metastasis-free survival is a valid surrogate endpoint for overall survival. A trial on high-risk patients will have to run for 8-10 years to collect a sufficient number of metastases to draw valid conclusions, so we can only look at this as an early signal.

Treatment of Pelvic Lymph Nodes

We know that the time to be able to see the first few cancerous pelvic lymph nodes is often several years, so 2.5 years of follow-up tells us little. The newly approved PSMA PET scans will be able to rule out the larger metastases (>5 mm), but will never be able to find metastases smaller than that. Waiting for visibility to make the decision to treat is a bad idea. By the time some lymph nodes are large enough or rapidly growing, the risk of spread outside the pelvic lymph node drainage area increases, and the hope of a cure may vanish.

The PSMA PET/CT is nevertheless worthwhile. While a negative scan does not change the treatment decision, a positive scan may detect occult metastases or pelvic lymph nodes that may benefit from a higher spot dose and more intense or longer hormone therapy.

We rely on validated formulas to tell us the probability that there are microscopic pelvic lymph node metastases. Two of the popular formulas are the Roach Equation (discussed here) and the Yale Formula (discussed here).

There is a risk of overtreatment. Many high-risk patients will never require pelvic lymph node treatment, and we are awaiting evidence (RTOG 0924) that such treatment will improve survival. As we have seen, bRFS is improved.

However, the only risk is that toxicity will be higher when the whole pelvis is treated. Murthy et al. showed that even at higher doses of pelvic lymph node radiation, there was no increase in acute toxicity, late gastrointestinal toxicity, and no deterioration in patient-reported quality of life scores.

Arguably, 25 extra IMRT treatments to the pelvic lymph nodes represent a patient inconvenience over the 5 SBRT prostate-only treatments. In the UCLA and Sunnybrook high-risk SBRT trials (discussed here), the pelvic lymph nodes may be treated (to 25 Gy) within the same 5 treatments. So far, with limited follow-up, cancer control is high and toxicity is low.

Hormone therapy intensification

The DART 01.05 GICOR trial proved that long-term (28 months vs 4 months) ADT improves survival in high-risk patients even when treated with dose-escalated IMRT. Nabid et al. proved that 18 months is often as good as 36 months. AASUR suggests that by including both Zytiga and Erleada, the duration of hormone therapy can be shortened. But the sexual and hormone quality of life did diminish. This raises questions that can only be answered in an expanded randomized clinical trial:

• Are all 3 medications (Zytiga, Erleada, and Lupron) necessary for the benefit? The ACIS trial found that adding Erleada increased radiographic progression-free survival in mCRPC patients. There was no such synergy found in adding Xtandi to Zytiga in this non-randomized trial.
• Do they add much to Lupron alone if whole pelvic radiation is given?
• Does Lupron alone for, say, 9 months, with whole-pelvic SBRT (as in the UCLA trial) afford the same benefit with less toxicity? And would Orgovyx instead of Lupron allow for earlier testosterone recovery?
• Can genomics (Prolaris or Decipher of biopsy tissue) identify patients who might benefit from the combined hormone therapy?