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.

Optimal prostate dose is also discussed:

SBRT dose escalation trial at Sunnybrook 

SBRT dose escalation trial at UTSW

Potters et al. trial

The multi-factorial nature of SBRT safety

Why we should care about standards of care

Escalated radiation dose doesn't improve 8-year overall survival in intermediate-risk men (but does it matter?)

Survival benefit of dose escalation for higher-risk patients

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.

Newest radiopharmaceutical: Th-227-PSMA-antibody

Bayer has announced a new clinical trial of the latest entry in the race for radiopharmaceuticals to treat prostate cancer, joining Lu-177-PSMA-617, Ac-225-PSMA-617, and I-131-MIP-1095. They are trying Thorium-227 attached to a PSMA antibody.

Thorium-227, like Ac-225, is an alpha-particle emitter. Alpha emitters are very powerful, but very short range, only killing cells that are 2 to 10 cells away from the cancer cell it attaches to. This may limit its toxicity, but may require higher doses for larger, more widespread tumors.  Beta emitters, like Lu-177, are less powerful, but the beta particle penetrates to a much greater depth, affecting about 125 cells. Researchers at the University of Heidelberg are experimenting with mixtures of the two.

The other part of the equation is the ligand that the radioactive atom is attached to and that attaches to the PSMA protein on the prostate cancer cell. Ligands include PSMA-617, PSMA-I&T, MIP-1095, and J591. Ligands may be small molecules, antibodies, or "minibodies." Bayer is using a proprietary antibody-type ligand that they developed for the purpose. Ligands that are more specific for PSMA have less toxicity.

On the other side of the ligand molecule, it must bind very tightly to the radioactive element. If it doesn't, the radioactive element might be released into systemic circulation where it can damage healthy cells. Heavy metals, like thorium, are attached relatively weakly by a process called "chelation," but some chelators are stronger than others. Researchers have so far been unsuccessful in developing a stable chelate for Ra-223 (the main ingredient in Xofigo, which is also manufactured by Bayer) to a PSMA ligand. However, Th-227 decays into Ra-223, so it is unknown if the thorium chelate will continue to hold as it decays. However, Bayer has already begun two clinical trials for Th-227 chelated to an antibody for non-Hodgkin's lymphoma since 2015, and for ovarian cancer and mesothelioma since April, which have not been terminated for excess toxicity. There is every reason to hope that the chelation complex they devised for the PSMA-antibody ligand holds up in biological systems. But if it doesn't hold chemically, it becomes the active ingredient in Xofigo, and may be doubly therapeutic in men with bone metastases.

This is a dose-finding (Phase 1) clinical trial among 108 patients with metastatic castration-resistant prostate cancer. They list 4 locations that will be recruiting: Memorial Sloan Kettering in NYC, Tulane (New Orleans), as well as locations in the UK and Finland.

SBRT has excellent outcomes for intermediate risk patients

Stereotactic Body Radiation Therapy (SBRT, or sometimes SABR or SHARP or CyberKnife) has had excellent 7-year outcomes in an update of the consortium study. Amar Kishan presented the results of his analysis at the ASTRO meeting today.

The consortium consisted of

1 Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, USA
2 Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA
3 Flushing Radiation Oncology Services, Flushing, NY, USA
4 21st Century Oncology, Fort Myers, FL, USA
5 Department of Radiation Oncology, Georgetown University, Washington, DC., USA
6 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
7 Division of Genesis Healthcare Partners Inc., CyberKnife Centers of San Diego Inc., San Diego, CA, USA
8 Swedish Radiosurgery Center, Seattle, WA, USA.
9 Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON,
Canada.
10 Section of Radiation Oncology, Virginia Mason Medical Center, Seattle, WA, USA
11 Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
12 Department of Radiation Oncology, University of Michigan
13 Scripps Health, 11025 North Torrey Pines Road, La Jolla, CA, USA
14 Virginia Hospital Center, 1701 N. George Mason Dr, Arlington, VA, USA

The meta-analysis covers 2,142 low (n=1,185) and intermediate-risk men treated with SBRT between 2003 and 2012. Intermediate risk men were further subdivided into "favorable intermediate risk" (n=692) and "unfavorable intermediate risk" (n=265) per the NCCN definition.

After a median follow-up of 6.9 years, the 7-year biochemical recurrence-free survival was:

• low risk: 95.5%
• favorable intermediate risk: 91.4%
• unfavorable intermediate risk: 85.1%
• all intermediate risk: 89.8%

Low risk patients and some of the favorable intermediate risk patients would probably be diverted to active surveillance today. The 7-year intermediate risk biochemical recurrence-free survival compares favorably with (note: this is not a randomized comparison, which is the only valid way of comparing):

• Surgery: favorable intermediate risk (PSA=6.0, T1c, GS 3+4, 33% cancerous cores): 79% (mean of 5 and 10-yr Progression-free survival) (1)
• Surgery: unfavorable intermediate risk (PSA=6.0, T1c, GS 4+3, 67% cancerous cores): 46% (mean of 5 and 10-yr Progression-free survival) (1)
• Hypofractionated IMRT (5 year):  85% (2)
• Conventional IMRT (5 year): 85% (2)
• Low dose rate brachytherapy: favorable intermediate risk (avg of 5 and 10-yr): 87% (3)
• Low dose rate brachytherapy: unfavorable intermediate risk (5-year): 81% (3)
• Brachy boost therapy: unfavorable intermediate risk (10 year): 92% (4)

7-year metastasis-free survival was:

• low risk: 99.9%
• favorable intermediate risk: 98.3%
• unfavorable intermediate risk: 97.0%
• all intermediate risk: 98.0%

There were no prostate cancer-related deaths.

Use of ADT and higher doses (doses ranged from 33 Gy to 40 Gy in 4 or 5 treatments) did not affect recurrence.

Acute (within 3 months of treatment) toxicity was low:

• Urinary toxicity Grade 2: 8.8% Grade 3: 0.6%
• Rectal toxicity Grade 2: 3.2% Grade 3: 0.1%

Late-term cumulative toxicity was low:

• Urinary toxicity Grade 2: 9.4% Grade 3+: 2.1%
• Rectal toxicity Grade 2: 3.9% Grade 3+: 0.4%

Late-term grade 3 or greater urinary toxicity of 2.1% compares favorably to other radiation monotherapies reported in other studies. For example:

• Low dose rate brachytherapy: 7.6% (5)
• High dose rate brachytherapy (3 fractions):11% (6)
• Hypofractionated IMRT (70 Gy/28 fx): 3.5% (7)
• Conventionally fractionated IMRT: 2.3% (7)
• Brachy boost therapy: 19% (8)

Late-term grade 3 or greater rectal toxicity of 0.4% compares favorably to other radiation monotherapies reported in other studies. For example:

• Low dose rate brachytherapy: 0.8% (5)
• High dose rate brachytherapy (3 fractions):1% (6)
• Hypofractionated IMRT (70 Gy/28 fx): 4.1% (7)
• Conventionally IMRT: 2.6% (7)
• Brachy boost therapy: 9% (8)

This 7-year analysis on a large group of patients from multiple sites, should make intermediate risk patients comfortable in choosing SBRT, especially if they are favorable intermediate risk. For patients who are unfavorable intermediate risk, brachy boost therapy affords incomparable oncological control, but at the risk of much higher late term urinary and rectal toxicity.

Whole pelvic salvage radiation + short-term ADT improves oncological results

We didn't expect to see this for another two years, but they hit their recruitment goal early and were able to provide 5-year results. Alan Pollack, the lead investigator, presented the preliminary findings of NRG Oncology/RTOG 0534 (or SPPORT) trial at the ASTRO meeting, and in Medpage Today. It proved that salvage whole pelvic radiation (sWPRT) with short term ADT  (STADT) is superior to either prostate-bed only salvage radiation (PBRT) or prostate-bed only salvage radiation with short term ADT.

They randomly assigned 1,792 men with a recurrence after prostatectomy in 2008-2015 at 460 locations in the US, Canada, and Israel to one of 3 therapies:

1. sWPRT+STADT
2. PBRT + STADT
3. PBRT

• ADT consisted of 4-6 months of a combination of an anti-androgen and an LHRH agonist starting 2 months before salvage radiation.
• Radiation dose to the prostate was 64.8-70.2 Gy at 1.8 Gy per fraction.
• Radiation dose to the pelvic lymph nodes was 45 Gy at 1.8 Gy per fraction.
• The treated pelvic lymph node area was per RTOG guidelines and did not include the recently recommended expansion. 

The oncological results were:

• 5-year freedom from progression (biochemical or clinical) was 89% for sWPRT+STADT, 83% for PBRT+STADT, and 72% for PBRT (all significantly different). They used a nadir+2 definition of biochemical progression because it correlated best with clinical progression.
• 8-year incidence of metastases was 25 for sWPRT+STADT (HR=0.52), 38 for PBRT+STADT (HR=0.64), and 45 for PBRT (sWPRT+STADT was significantly better than the other two)

The reported toxicity results were:

• GI grade 2 or higher: 7% for sWPRT+STADT vs. 2% for PBRT
• Bone marrow grade 2 or higher: 5% for sWPRT+STADT vs. 2% for PBRT
• Bone marrow grade 3: 2.6% for sWPRT+STADT vs. 0.5% for PBRT
• Late term bone marrow grade 2 or higher was 4% for sWPRT+STADT

There were some caveats. The researchers found that the benefit of salvage whole pelvic treatment and ADT was not maintained in men with very low PSA. There are further analyses expected based on patient risk characteristics and genomic biomarkers. We previously saw in a retrospective study that prostatectomy Gleason score had a significant influence. With better PET scans now, we can have more assurance that whole pelvic radiation is necessary. But at very low PSA (<0.2), even our best PET scans may not find the cancer. Also, it may be that long-term ADT may improve results even further, and that dose escalation may improve results. While this changes the standard of care for many men with persistent PSA and recurrences after prostatectomy, the patient and his radiation oncologist still must rely on judgment.