SPPORT trial: whole pelvic salvage radiation + short-term ADT after failed surgery can be a curative option

 In 2018, we saw the early results of the SPPORT randomized clinical trial (see this link). Now Pollack et al. has published the full results. To review:

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. PBRT (prostate-bed radiation only)
2. PBRT + STADT (prostate-bed radiation + short-term ADT)
3. sWPRT + STADT (salvage whole pelvic radiation + short-term ADT)

• 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 bed 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. (There is also an expansion of the prostate bed, as discussed here)
• The sample size was powered to detect progression-free survival, but not metastases, prostate cancer mortality, or overall survival. 8 years of follow-up is insufficient for those other endpoints.

The oncological results were:

• 8-year freedom from progression (biochemical or clinical) was 77% for sWPRT+STADT, 72% for PBRT+STADT, and 61% for PBRT (all significantly different, regardless of initial ADT, Gleason score, or stage). They used a nadir+2 definition of biochemical progression because it correlated best with clinical progression.
• At lower PSA (≤ 0.35), Group 3 did no better than Group 2, so widening the treatment area had no effect. Both groups did better than Group1, so ADT had a significant effect.
• At higher PSA (> 0.35), Group 3 was better than Group 2, but the difference was not statistically significant. Both groups did better than Group 1, indicating ADT effectiveness.
• 4 vs 6 months of ADT did not matter. It reduced the occurrence of local and regional metastases.
• Widening the treatment area reduced the long-term rate of local and regional metastases.
• 8-year incidence of metastases was 69 (12%) for PBRT (HR=0.71), 56 (10%) for PBRT+STADT (HR=0.74), and 41 (7%) for sWPRT+STADT (HR=0.52). sWPRT+STADT was significantly better than the other two.

The physician-reported acute toxicity results show some small early adverse effects of ADT and the wider treatment area:

• GI grade 2 or higher: 7% for sWPRT+STADT vs. 4% for PBRT+STADT vs. 2% for PBRT
• GU grade 2 or higher: 12% for sWPRT+STADT vs. 12% for PBRT+STADT vs. 9% for PBRT
• Bone marrow grade 2 or higher: 5% for sWPRT+STADT vs. 2% for PBRT+STADT vs. 2% for PBRT
• Bone marrow grade 3: 2.6% for sWPRT+STADT vs. <1% for PBRT+STADT vs. 1% for PBRT

The physician-reported late toxicity results show that late toxicity was not influenced by ADT or whole pelvic RT:

• GI grade 2 or higher: 9% for sWPRT+STADT vs. 10% for PBRT+STADT vs. 10% for PBRT
• GU grade 2 or higher: 40% for sWPRT+STADT vs. 35% for PBRT+STADT vs. 37% for PBRT
• Bone marrow grade 2 or higher: 4% for sWPRT+STADT vs. 2% for PBRT+STADT vs. 4% for PBRT

This RCT proved that whole pelvic salvage radiation with 4-6 months of ADT is the preferred salvage treatment.

In contrast to a previous trial (RTOG 9601) that told us that ADT can be safely avoided if PSA<0.7, this trial suggests at least 4 months of ADT and whole pelvic treatment. The reason for the difference in recommendations is due to the choice of endpoint. SPPORT is telling us that if we are willing to put up with 4 months of ADT and some extra short-term toxicity from the wider field of radiation, a cure is likely. RTOG 9601 tells us that if your PSA<0.7, you aren't likely to die if you don't get the extra short-term hormone therapy, but you may have to have lifelong ADT eventually. It will always be a managed disease. Patients should acknowledge these trade-offs and discuss with their doctors.

Results may possibly be improved further with:

• Better patient selection using PET scans (PSMA, Axumin, or NaF)
• Extra radiation to the prostate bed
• Boost doses to cancer detected with a PSMA PET scan (if PSA> 0.5 - but do not wait!)
• Selection of patients who would benefit from treatment intensification using a Decipher test
• Hormone therapy intensification in select patients (as in this clinical trial)

Evidence for Dose Escalation in Adjuvant/Salvage Radiation

It is well known that prostate cancer is relatively radio-resistant compared to other kinds of cancer. While dose escalation (most recently by increasing the biologically effective dose using hypofractionated dose (more that 2.0 Gy per session) delivery or brachytherapy boost therapy) has become the mainstay in primary radiation therapy, doses delivered for adjuvant or salvage radiation has stayed about 10 Gy lower. Recently, Dr. King's analysis of the dose responsiveness of salvage radiation questioned this supposition (see this link). While his mathematical arguments provide us with intriguing plausibility, only clinical evidence from a randomized clinical trial can change practice.

We now have Level 1 evidence that expanding the adjuvant/salvage treatment field to include the pelvic lymph nodes improves the oncological outcomes in men with higher PSA at the time of salvage radiation.

Link et al. conducted a small, retrospective study among 120 locally advanced (stage T3/4) post-prostatectomy patients at the University of Heidelberg between 2009 and 2017. All were lymph node negative.

• 43 received whole pelvic radiation therapy (WPRT)- 62% received 79.3 Gy to the prostate
• 77 received radiation to the prostate bed only (PBO)- 70% received 79.3 Gy to the prostate
• Biologically equivalent dose (2 Gy) to the prostate was 79.3 Gy ("high dose") if they had positive margins or PET/CT/MRI imaging-detectable prostate bed tumors (62% of patients), 71.4 Gy ("low dose") if they had negative margins (38% of patients).

Median freedom from biochemical failure was:

• longer among those who got the higher dose: 76 months vs 21 months
• longer among those who received WPRT vs PBO: 68 months vs 32 months

There is a lot of overlap in treatments, so it is impossible to tease out the effect that each had on the oncological outcomes. Almost all of those who received the escalated dose also had positive margins - a known factor for predicting success of adjuvant/salvage radiation. Also, almost all men who had adjuvant radiation had positive margins and dose escalation - adjuvant radiation has proven to be more successful than "wait-and-see" in 3 major randomized clinical trials.

Toxicity increased with both dose and size of the treatment field. Grade ≥ 2 toxicity was reported by:

• 3.4% among those who received low dose and PBO
• 12.5% among those who received high dose and PBO
• 15.4% among those who received low dose and WPRT
• 36.7% among those who received high dose and WPRT
• No reports of Grade 3 gastrointestinal toxicity
• 13% Grade 3 urinary toxicity among high dose patients, none among low-dose patients

This is a far cry from the randomized clinical trial we need for practice-changing dose escalation for adjuvant/salvage radiation. However, we can't rule out that there is no oncological benefit to dose escalation. It remains unknown what proportion of these high-risk patients would have done just as well with lower doses and smaller treatment fields. The increase in toxicity with dose and treatment field means that patients ought not jump into this without understanding the risks and discussing them with their radiation oncologists.

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.

Salvage SBRT after Prostatectomy

UCLA has announced a new clinical trial using SBRT for treating recurrent prostate cancer after failure of initial prostatectomy. This is the third such trial in the LA area, adding to the ones at USC and  City of Hope (no longer recruiting). The advantages to the patient are completing salvage radiation in just 5 treatments, and at a lower cost. But there are many issues that the lead investigators, Amar Kishan and Chris King, explored in a very detailed document that they kindly allowed me to see. The hope is that the increased biologically effective dose possible with extreme fractionation will increase cure rates without adding undue toxicity.

Eligibility

Patients are eligible if they had adverse pathological findings (i.e., Stage T3/4, positive margins, Gleason score 8-10, tertiary pattern 5), or PSA rising over 0.03 ng/ml. They are excluding anyone who exhibits distant metastases on a bone scan (M1) or positive pelvic lymph nodes discovered by dissection (pN1). They are allowing patients with non-surgical evidence of pelvic lymph node invasion (i.e., suspected because of a CT or a PET/CT).

Radiation Dose / adjuvant ADT

The treatment plan is:

• All patients will receive 34 Gy in 5 fractions to the prostate bed. 
• There may be a simultaneous boost dose of 40 Gy to any detected tumors in the prostate bed.  
• Optionally, they will also receive 25 Gy in 5 fractions to the pelvic lymph nodes. 
• Optionally, they will also receive 6 months of ADT beginning 2 months before radiation begins. 

While whole pelvic radiation and adjuvant ADT improve salvage radiation outcomes on the whole (see this link), they may not be necessary in all cases. A recent analysis suggested that adjuvant ADT only benefits those with post-prostatectomy PSA ≥ 0.4 ng/ml, Gleason score 8-10, Stage T3b/4, and those with high Decipher scores (> 1 in 3 probability of distant metastases in 10 years).

The prostate bed dose is biologically equivalent to 85 Gy using conventional fractionation (about 1.8 Gy per fraction). It is much higher than the typical salvage radiation dose of 67 Gy - 72 Gy in 37-40 fractions. It also exceeds by about 9% the dose used in a trial of moderate hypofractionation (discussed here). At the last ASTRO meeting, Dr. King presented the rationale for increasing the salvage radiation dose (see this link).  At the time, he proposed a randomized clinical trial using a dose of 76 Gy with conventional fractionation. The new protocol far exceeds that dose on the basis of biologically effectiveness, but they will compare outcomes to historical controls. The goal is to achieve a 5-year biochemical recurrence-free survival rate of 72%, compared to the historical level of 56%.

Toxicity

Salvage SBRT isn't just another form of salvage IMRT; IMRT is more forgiving. With IMRT, if there is a small misalignment, it is not a big deal -- the dose per fraction is small enough that a target miss caused by organ motion will not materially affect outcomes and will average out over time.

• Only devices that continuously track prostate bed motion during, and not just at the start of, each treatment, and that operate with extremely fast treatment times may be able to avoid all of the geographic misses. Image guidance is complicated when there is nothing for fiducials to grab onto.  This becomes an important consideration only at higher dose rates.
• Although the biologically effective dose (BED) for oncological control is higher with the SBRT protocol, the BED to healthy tissues (which causes toxicity) is lower. 
• For the tissues that may cause acute toxicity, the BED is a third lower compared to a 72 Gy conventionally-fractionated treatment. In a recent trial of 70 Gy salvage radiation, acute grade 2 and 3 urinary toxicity was 18%; acute grade 2 and 3 rectal toxicity was 18% as well.
• For the tissues that may cause late-term toxicity, the BED is about the same. Serious late-term toxicity was a rare event when 76 Gy was used for salvage in one study, but late term grade 2 toxicity was about 20% urinary toxicity and 8% for rectal toxicity. It is unknown whether the late-responding tissues of the bowels and urinary tract will suffer increased damage from the higher dose rates after longer follow-up.

SBRT as a primary treatment is different from SBRT as a salvage treatment.  There are also several considerations that arise more in the salvage radiation therapy setting than in the primary therapy setting:

• The bladder and rectum are no longer shielded by an intact prostate, so they are potentially exposed to greater spillover radiation. The prostate bed without the prostate is highly deformable, and rectal distension can change its shape markedly within seconds during the treatment. This increases the amount of toxic radiation absorbed by healthy tissues.
• The scar tissue of the anastomosis may become inflamed, leading to a higher risk of urinary retention or tissue destruction.
• The bladder neck, which may be spared during primary radiation and surgery, receives a full dose during salvage radiation therapy, increasing the probability of bladder neck contracture, urethral strictures, pain and incontinence. These problems may be amplified at higher doses per treatment.
• Erectile function is probably already impaired from the surgery. Neurovascular bundles, if spared by surgery, are far more exposed during salvage radiation.

We have had a couple of cautionary cases where SBRT toxicity has been extraordinarily high. In one, it was because the delivered radiation dose was too high. In the other, there may have been multiple causes.

There has been a study where conventionally fractionated salvage IMRT with a dose as high as 80 Gy has been used with low toxicity. A recent study using moderate hypofractionation for salvage (51 Gy/ 17 fx) also boasted low toxicity levels among treated patients.

They will monitor both physician-reported toxicity and patient-reported toxicity (urinary, rectal, and sexual). If the rate of grade 3 (serious) toxicity is higher than 20%, accrual will be halted and the study subjected to careful review. If the rate is higher than 30%, the study will be terminated.

Dose Constraints

The investigators have put together a set of very tight dose constraints for organs at risk. Organs at risk include the bladder, the front and back of the rectum, the small intestines, the penile bulb and the femoral head. They also included "point dose constraints": the maximum radiation exposure to even a millimeter of the organ at risk. Because of individual anatomy, it may not always be possible to simultaneously meet all dose constraints. In those cases, the physician will decide if the deviation is material, and if it is, he may lower the dose as low as 30 Gy.

Image Guidance

The prostate bed consists largely of loose and highly deformable tissue. Although some radiation oncologists (e.g., at UCSF) use fiducials or transponders for salvage image guidance, most find that they do not stay in place. This has not been a big issue for salvage IMRT because a few "misses" will not contribute materially to toxicity, but it may be a larger issue for salvage SBRT. One way around this is to have the doctor monitor the position of the soft tissue throughout each treatment, and manually realign the beams whenever the position of the tissues deviates from the planning image. The problem is that  manual realignment is time consuming. The patient is lying on  the bench with a full bladder, which may be difficult to hold in. Also, the more time that passes during a treatment, the more opportunity for bowel motion to occur. The lack of intrafractional image guidance remains a concern in this clinical trial that the investigators are well aware of.

A related issue occurs when the pelvic lymph nodes are simultaneously treated. The lymph nodes may move independently of the prostate bed, so it may be impossible to hit both areas simultaneously with pinpoint accuracy. The investigators are using the pelvic bones as landmarks.

Most importantly, all patients must have a full bladder to lift it up and help anchor organs in place. in addition, enemas are required before each treatment, and if the bowels are at all distended, treatment will be discontinued.

Risks

As with any clinical trial, patients take a risk in trying a new treatment. There is also a learning curve that doctors go through in trying out a new therapy.  I, myself, chose to participate in a clinical trial of primary SBRT when there were only 3 years of reported data. I judged the potential benefits worth the risk for me. It was also important to me that the treating radiation oncologist (Dr.King) had been using SBRT for prostate cancer longer than anyone else. Every patient should be well aware of the risks before agreeing to participate in a clinical trial. Patients who are looking for a shorter duration treatment with less toxicity risk may wish to be treated at the University of Wisconsin or in a clinical trial at the University of Virginia (discussed here).

When is whole pelvic radiation needed for salvage?

Patients who elect to have post-prostatectomy radiation for recurrent prostate cancer face a couple of important decisions:

(1) Should the radiation be limited to the prostate bed (PBRT)? OR
(2) Should one treat all the pelvic lymph nodes at the same time (whole pelvic radiation - WPRT)? And if so, is the oncological outcome likely to be better if one has androgen deprivation therapy (ADT) along with it?

There is an ongoing prospective randomized clinical trial (RTOG 0534) to help answer these questions. But results are not expected until the end of 2020. Meanwhile, the best we can do is look at how patients have done in the past. Ramey et al. conducted a retrospective analysis of 1861 patients treated at 10 academic institutions between 1987 and 2013. The treatments and patient characteristics were as follows:

• All had post-prostatectomy PSA> 0.01 ng/ml (Median was 0.5 ng/ml)
• All had post-prostatectomy Gleason scores ≥ 7
• None had detected positive lymph nodes
• 1366 had PBRT without ADT,  250 with ADT
• 176 had WPRT without ADT, 69 with ADT
• Median salvage radiation dose was 66 Gy
• More than half of GS 8-10 patients got ADT, whereas most GS 7 patients did not
• 60% had extraprostatic extension
• 21% had seminal vesicle invasion
• 60% had positive surgical margins

After a median follow-up of 51 months, the 5-year freedom from biochemical failure outcomes are shown in the following table.

             5-Year Freedom from Biochemical Failure

	PBRT	WPRT	TOTAL
With ADT	51%	66%	55%
Without ADT	48%	60%	50%
TOTAL	49%	62%	51%
Among GS 7:
With ADT	56%	70%	59%
Without ADT	52%	66%	54%
TOTAL	53%	67%	56%
Among GS 8-10:
With ADT	45%	64%	49%
Without ADT	34%	44%	35%
TOTAL	37%	53%	44%

WPRT with ADT had the best outcomes in total and in each Gleason score category. Two-thirds of salvage patients had 5-year cancer control with the combination, whereas only about half had oncological control without them. The differences were especially marked among those with GS 8-10. There was significant improvement even in men with GS 7; however, they did not have the data to ascertain whether they were GS 3+4 or GS 4+3. Adjuvant ADT improved outcomes whether it was used in conjunction with WPRT or PBRT. On multivariate analysis, both WPRT and ADT independently increased freedom from biochemical failure. Higher radiation dose, lower PSA, lower Gleason score, Stage T2, and positive surgical margins decreased the risk of failure.

Neither WPRT nor ADT made any difference in the rate of metastases, which were low at 5 years post-prostatectomy.

Toxicity and quality of life, which would be the only reasons not to give WPRT and ADT to all salvage radiation patients, were not evaluated in this study. Also lacking were data on duration and type of adjuvant ADT

This study is congruent with a couple of retrospective studies (see this link and this one), but incongruent with a couple of other retrospective studies (see this link and this one). The present study is the largest and most recent dataset of them, and corrects for the effects of other variables in a way that the two opposing studies did not.

We saw previously that adjuvant ADT has been proven in a randomized clinical trial to improve oncological outcomes of salvage radiation after prostatectomy (see this link).

While we await the more definitive data from RTOG 0534, this builds the case that both WPRT and ADT should be included in the salvage radiation treatment of men with prostatectomy-diagnosed Gleason scores of 8-10, and at least some of those with Gleason score of 7. There are several open questions:

• Is there a benefit for GS 3+4, or only for GS 4+3 or higher?
• Is there a benefit when higher salvage radiation doses (70-72 Gy) are used, or with hypofractionated protocols that raise the biologically effective dose?
• What is the optimal duration of adjuvant ADT?
• Would any of the newer hormonal therapies (e.g., Zytiga or Xtandi) or other systemic therapies improve outcomes?
• What are the trade-offs with toxicity and quality of life?
• What is the optimal treatment field for WPRT, and should it vary with individual anatomy and comorbidities, given its potential toxicity?
• Can we use the newer PET scans or USPIO MRI to help decide if WPRT is necessary?
• Can we identify any subsets (e.g., low PSA, stage T2, GS 3+4) that would not benefit from the additional treatment?