Salvage SBRT for local recurrence after primary radiation therapy (RT)

This is the second of a two-part commentary. In Part I, we looked at studies that identified the site of failure after primary radiation treatment, and learned that over half of radiation failures, at least for IMRT and LDR brachytherapy (the two most popular kinds of primary radiation) were local (prostate/seminal vesicles) recurrences only. In Part II, we look at how SBRT is being used to treat such local recurrences.

Most of us have heard the oft-repeated aphorism from urosurgeons: If you choose radiation first, you can’t have surgery afterwards. That is what Stephen Colbert would call truthy. It’s certainly true that few surgeons are skilled enough to do that very delicate, painstaking surgery, but there are a handful of very high volume surgeons who have the experience to do it well, and get good results. (See this link.)

Other than a rock-star salvage surgeon, the salvage options after primary radiation fall into two categories: salvage ablation and salvage radiation. Salvage ablation after RT has been mostly limited to cryotherapy, although other kinds like HIFU and laser ablation may prove useful. Salvage radiation after RT has been limited to brachytherapy – either low dose rate (seeds) or high dose rate (temporary implants). IMRT cannot be used after previous radiation because of excessive dose to nearby organs. Salvage therapies may be focal (treating only the site of the recurrence), hemi-gland (treating only the lobe of the recurrence), or whole gland. The wider the treated volume, the greater the chance at cancer control, but the greater the risk of side effects. We now have some early data on salvage SBRT for local recurrences after radiation.

Fuller et al. reported on a prospective clinical trial among 29 patients with biopsy-proven local recurrence. All of them were re-treated from 2009 to 2014 with SBRT.
The inclusion criteria were:

• ·      Screened for distant and nodal metastases with CT or MRI scans
• ·      At least 2 years from primary treatment (Median 88 months)
• ·      Median primary EBRT dose of 73.5 Gy (range 64.8-81 Gy)

o   1 patient had received primary LDR brachytherapy, 1 had prior SBRT

• ·      No lasting side effects >grade 1 from the primary therapy

o   48% had chronic grade 1 rectal or urinary side effects

At the time of salvage, the patient profile was:

• ·      Median age: 73
• ·      Stage at salvage:

o   T1c/T2a: 20 patients

o   T2b/T2c: 8 patients

o   T3: 1 patient

• ·      Gleason score at salvage:

o   GS 6: 6 patients

o   GS 7: 12 patients

o   GS 8: 6 patients

o   GS 9: 5 patients

• ·      Median PSA was 3.1 ng/ml
• ·      7 had relapsed in spite of ADT

The salvage SBRT consisted of:

• ·      The CyberKnife system with fiducials was utilized.
• ·      Prescribed dose was 34 Gy in 5 fractions to the prostate
• ·      Peripheral zone and other areas of the prostate received larger doses
• ·      No treated margin outside of the prostate
• ·      No mention of boost to biopsy-identified areas
• ·      ADT was not used

With a median followup of 24 months:

• ·      PSA decreased to 0.16 ng/ml
• ·      2-yr biochemical disease-free survival was 82%

o   No local failures detected

o   No distant failures detected

• ·      Among the 4 recurrences:

o   3 were GS 6/7, 1 was GS 8/9

o   2 were stage T1c, 2 were stage≥T2b

o   3 had original PSA≤5.0, 1 had PSA> 10.0

o   1 had prior ADT

• ·      Late urinary toxicity:

o   Grade 2: 3 patients (10%)

o   Grade 3: 1 patient (3%) required catheter

o   Grade 4: 1 patient (3%) required cystoprostatectomy

o   The patient with prior LDR brachytherapy had severe urinary toxicity.

o   The patient with prior SBRT had only mild, transient urinary toxicity.

• ·      No acute or chronic grade 2 or higher rectal toxicity.
• ·      Among the 10 previously potent patients, 4 (40%) retained full potency

Fuller is cautiously optimistic, noting the limited sample size and limited length of follow-up. His early findings are comparable to those observed with salvage HDR brachytherapy. While PSA response and the recurrence rate so far are excellent, there are no obvious risk factors that predict failure. While toxicity was acceptable given the high lifetime dose of radiation, there were no obvious predictors of toxicity. The previous radiation dose and time since primary treatment may be important considerations. He notes that salvage radiation of previous LDR brachytherapy patients should be approached with caution.

Zerini et al. report on 32 patients who received salvage SBRT after either primary radiation (in 22 patients) or as a second salvage to the prostate bed after primary prostatectomy (in 10 patients). The patients were treated in Milan, Italy between 2008 and 2013. Among the 22 patients who received salvage after primary radiation, the median PSA was 3.9, and the median age was 73.

• ·       Only 3 patients had been previously treated with brachytherapy.
• ·       C11-Choline PET/CT was used in 88% to identify relapse.
• ·       47% were confirmed by biopsy
• ·       Some received a multiparametric MRI scan as well.
• ·       Patients were re-treated at a median of 115 months from first diagnosis.
• ·       Minimum follow-up was 12 months.

The treatment details for salvage SBRT after primary RT were as follows:

• ·       30 Gy or 25 Gy in 5 fractions to prostate and seminal vesicles
• ·       Treatment margins were 3 mm posteriorly and 5 mm elsewhere.
• ·       36% had adjuvant ADT
• ·       Several treatment platforms were used
• ·       Intra-fractional motion was tracked with fiducials.

After a median follow-up of 21 months:

• ·       12.5% had died
• ·       41% had no evidence of disease
• ·       47% had biochemical or clinical evidence of disease
• ·       38% had clinical progression
• ·       25% had out-of-field progression
• ·       12.5% had local progression

Among the 22 patients re-treated after primary RT:

• ·       Grade 2 acute urinary toxicity: 2 patients (9%)
• ·       No grade 2 or higher late urinary toxicity
• ·       No grade 2 or higher acute or late rectal toxicity

This study used markedly lower radiation doses compared to the Fuller study. That probably explains much of the higher local failure rate observed here – 12.5% vs. 0%. Fuller also more carefully selected eligible patients for his prospective trial compared to this retrospective study, and none were previously treated postprostatectomy. On the other hand, toxicity was extremely low in this study.

(Update 3/2017) Mbeutcha et al. reported on 10 patients treated with whole-gland high dose rate brachytherapy and 18 patients treated with focal SBRT after biopsy-confirmed local failure (and C-11 Choline PET ruled out distant metastases) after primary IMRT. The patients were treated in Nice, France from 2011 to 2015. The radiation dose with 35 Gy in 5 fractions. After 14.5 months of median follow-up among those receiving the focal salvage SBRT, 56% remained free of PSA recurrence.

(update 12/2017) Loi et al. reported on 50 patients treated with focal SBRT after F18 Choline PET and MRI-confirmed local failure after EBRT. The patients were treated at the University of Florence. 11 patients had adjuvant ADT. At 4 months after focal treatment, 80% were free of recurrence.

(update 8/2019) Pasquier et al. reported on 100 patients treated with salvage SBRT for biopsy-proven local recurrence after EBRT at 7 centers in France.

• Recurrence sites were located by mpMRI and choline PET scans. 
• The median dose to the prostate was 36 Gy in 6 fractions. 
• 34% had adjuvant ADT for a median of 1 year.
• Median time to recurrence was 7.5 years

After 29 months of follow-up:

• 3-year (second) recurrence-free survival was 55%
• Acute Grade 2+ rectal toxicity was 0%
• Acute Grade 2+ urinary toxicity was 9% (Grade 3 was 1%)
• Late-term Grade 2+ rectal toxicity was 1%
• Late-term Grade 2+ urinary toxicity was 21%

(update 2/23) Cozzi et al. reported on 20 radio-recurrent men after PET and MRI and biopsy-proven recurrence treated with salvage SBRT+ADT.

• 2 yr PFS was 81.5%
• 4/20 patients had a pelvic lymph node recurrence for which they received further SBRT
• No serious (Grade 3) acute or late-term toxicity
• Grade 2 acute urinary toxicity occurred in 10%
• Grade 2 late-term urinary toxicity occurred in 10%

(update 3/29/2023) Nikitas et al. reported a retrospective study of 11 patients who failed LDR brachytherapy and received whole gland SBRT salvage therapy.

• 3 yr PFS was 70.1%
• Median time to recurrence was 2 years
• Late grade 2 and 3 urinary toxicity were 36% and 9%, respectively
• Late grade 2 and 3 rectal toxicity were 0% and 9%, respectively

NIH is currently running a free clinical trial in which all patients will be diagnosed with a DCFPyL PET scan before and after treatment. Details here.

While salvage SBRT seems to be an excellent re-treatment alternative after local failure of primary radiotherapy, there are many outstanding questions, among them:

• ·       Will these early results hold up with larger numbers of patients and longer follow-up?
• ·       What dose is best for providing cancer control while limiting toxicity?
• ·       Will the low toxicity be maintained among patients who were initially treated with escalated doses? What about patients initially treated with brachytherapy?
• ·       Is there a minimum wait time between treatments?
• ·       What margins and dose constraints are optimal? Can the urethra be better spared?
• ·       Should simultaneous integrated boosts or higher doses be used within areas of the prostate?
• ·       Is adjuvant ADT beneficial?
• ·       To improve patient selection, should more advanced imaging be used to detect distant metastases?
• ·       Is there a role for genetic analysis of local recurrences?
• ·       Should tumor hypoxia be ascertained at biopsy?
• ·       What are the relative benefits of salvage SBRT vs. salvage brachytherapy and salvage ablation?
• ·       Can SBRT be used as a focal or hemi-ablative salvage therapy?

Site of recurrence after primary radiation therapy

This is the first of a two-part commentary. In this part, we look at studies that identified the site of failure after primary radiation treatment. In next part, we will look at how SBRT is being used to treat such local recurrences.

Before any kind of treatment is given for a recurrence only detected via rising PSA, it’s important to assure that it is indeed only a local recurrence. If there are already distant metastases, local salvage treatment would only create side effects without cancer control. In the past, we only had bone scans and CT scans that could detect only the larger metastases. New imaging technologies are enabling us to better assess the recurrence site.

Hannequin et al. posted the results of their study (abstract 23) at last week’s Genitourinary Conference. The authors retrospectively looked at 89 patients treated in Paris, France between 2010 and 2014 with either brachytherapy (23 patients) or EBRT (66 patients) and who had a biochemical recurrence detected as a rising PSA of at least 2.0 ng/ml over its lowest level.  The patients were classified at diagnosis as favorable risk (28%), intermediate risk (39%) or unfavorable risk (33%). They all had an 18-FCH-PET scan and may have had a multiparametric MRI as well. In 20 patients (22.5%), no target lesion could be clinically identified. Among the 69 patients in whom a clinically detected recurrence was identified, the recurrence site was as follows:

• ·      Local recurrence in 35 patients (51%)
• ·      Lymph node recurrence in 22 patients (32%)
• ·      Distant metastases in 12 patients (17%)

All of those 57 patients with local or lymph node recurrence (83%) were deemed eligible for salvage radiation, but only 17 (25%) could have it. The reasons for not having salvage radiation included advanced age, poor performance status, extensive disease, and patient refusal.

Zumsteg et al. published a retrospective analysis of 2,694 patients treated with external beam RT (IMRT or 3D-CRT) at Memorial Sloan Kettering Cancer Center between 1991 and 2008. The patient diagnosis and treatment characteristics were as follows:

• ·      Risk category:

o   Low risk: 22%

o   Intermediate risk: 48%

o   High risk: 30%

• ·      Median age: 69
• ·      Adjuvant ADT received: 54%, median of 6 months
• ·      Radiation dose received:

o   75.6 Gy (17%)

o   79.2-82.8 Gy (43%)

o   86.4 Gy (40%)

Local recurrence (prostate and seminal vesicles) was clinically detected mostly (71%) via biopsy, the rest radiographically (MRI or PET scan). Lymph node recurrences were detected by CT scan, and distant recurrences were clinically detected via biopsy, by radiographic response to ADT, or by rapidly rising PSA during the castrate-resistant phase. After 83 months of followup overall, and 111 months of followup on clinically recurrent patients:

• ·      22.6% had a biochemical recurrence, defined as nadir+2
• ·      17.6% had a clinically detected recurrence.
• ·      Recurrence by risk category:

o   Low risk: 5.8%

o   Intermediate risk: 13.4%

o   High risk:  32.8%

• ·      Recurrence by radiation dose:

o   75.6 Gy: 29.1%

o   79.2-82.8 Gy: 14.6%

o   86.4 Gy:  15.8%

• ·      Recurrence was also higher in men under 70, higher stage, PSA>10, >50% positive cores.

Among those in whom a clinical recurrence was detected within 8 years of primary treatment, the site of the first recurrence was as follows:

• ·      Local recurrence in 55%

o   74% in low-risk recurrent patients

o   68% in intermediate-risk recurrent patients

o   45% in high-risk recurrent patients

o   in 87% of local recurrences, it was the only recurrence site

• ·      Pelvic lymph nodes (PLN) in 21%*

o   None in low-risk recurrent patients

o   in 38%, of PLN recurrences, it was the only recurrence site

• ·      Abdominal lymph nodes in 9%
• ·      Thoracic lymph nodes in 2%
• ·      Bone in 34%

o   40% in high-risk recurrent patients

o   in 66% of bone recurrences, it was the only recurrence site

• ·      Viscera in 2%

*Patients who presented with enlarged nodes were excluded, and no one received whole pelvic radiation.

The authors also note that a first isolated PLN recurrence was a rare event among all the men treated with EBRT, only occurring in 1.5% of them.

The site of recurrence was strongly correlated with prostate cancer-specific mortality. Compared to locally recurrent prostate cancer, the risk of prostate cancer death after a median of 111 months of followup was:

• ·      4.2 times higher for lymph recurrences
• ·      8.1 times higher for bone recurrences
• ·      9.6 times higher for multi-organ/visceral recurrences

In fact, after accounting for the site of recurrence, only the Gleason score, but none of the other risk factors (e.g., PSA kinetics, stage, age, time to recurrence), predicted prostate cancer mortality. This, and the fact that a first recurrence site was often the sole recurrence site, suggests that there are different types of prostate cancer (phenotypes) with characteristic patterns of spreading and characteristic virulence.

The authors draw 3 conclusions:

“1) The prostate is the most common initial site of recurrence in patients in all risk groups with an increasing absolute incidence that correlates with increasing NCCN risk group.  

2) Isolated PLN relapse is rare in all patients, including those at high risk treated without elective PLN irradiation, at least when using CT for detection.

3) Tumors in many patients display a tropism for specific anatomical compartments and these anatomical patterns of recurrence independently predict prostate cancer specific mortality after clinically detected recurrence.

Unfortunately, their report doesn’t show the time to first recurrence broken down by recurrence site. It may be that the much shorter followup in the French study (patients were treated 2-6 years ago) may explain the lower incidence of bone metastases in that study. Detection methods may explain the differences as well.

In both studies, more than half of the recurrences after primary radiation therapy were local and were at least potentially treatable with salvage therapies. That may not hold true for other kinds of radiation. There isn’t a lot of data on recurrence sites, but the higher biologically effective doses available with SBRT, HDR monotherapy, and multi-modal radiation may be better able to overcome the more radio-resistant cells. In a recent commentary, we saw that a novel kind of radiation, called Carbon Ion Radiotherapy, could kill cancer cells even in a low-oxygen (hypoxic) tumor environment.

The table below shows the range of biologically effective doses for various radiation modalities, and the percent of local failures in all treated patients (not just those with a recurrence), broken out by risk group where available.

Percent Local Failures by Risk Group

	EBRT	SBRT	HDR brachy monotherapy	EBRT+HDR brachy boost
Relative biologically effective dose*	.89-1.02	1.06-1.17	1.27-1.36	.97-1.17
Low Risk	4%	0.9%	2.5%	1%
Intermediate Risk	9%	2.6%		1%
High Risk	15%	7%		9%
Followup	9 years	6/7 years	10 years	4 years
Reference	Zumsteg et al.	Katz and Kang Katz and Kang	Hauswald et al.	Kamrava et al.

*Relative to 80 Gy of IMRT for cancer control

The local failure rates seem to be higher for EBRT than for SBRT, HDR brachy monotherapy, or HDR brachy boost therapy. Only a randomized comparative trial can decide what relative role biologically effective doses, radiation intensity, patient selection, and detection techniques play in determining the extent of local control. It would be useful to know as well whether genetic tests like Prolaris or Oncotype Dx can predict local response to radiation, and whether there are identifiable subtypes that metastasize to lymph nodes, bones or viscera. Better detection of local and distant recurrence is needed as well.

In the next commentary, we will look at how SBRT is being used in salvage treatment of those isolated local recurrences.

written January 13, 2016

SBRT has equivalent toxicity with 5 treatments and 12 treatments

Lukka et al. reported one-year outcomes of the RTOG 0938 trial designed to test whether SBRT done in 5 treatments of fractions has equivalent and acceptable toxicity compared to SBRT in 12 fractions.

This was a multi-institutional US /Canadian study among 246 low risk men. They were randomly assigned to one of two SBRT treatment regimens:

• Arm 1: 36.25 Gy delivered in 5 fractions twice a week for 2 ½ weeks.
• Arm 2: 51.6 Gy delivered in 12 fractions 5 days a week for 2 ½ weeks.

These doses are approximately equivalent in biologically effect for cancer control and in their expected effect on healthy tissues. Men were allowed to be treated on several different SBRT platforms, including CyberKnife, VMAT and protons.

This is the planned 1-yr quality-of-life analysis, with future analyses to be performed after 2 and 5 years.  The EPIC questionnaire was used to assess bowel, urinary, and sexual quality-of-life.

•     Bowel changes > 5 points are considered clinically significant.

o   Any such change affecting ≤ 35% of men was considered to be acceptable.

o   Any such change affecting ≥ 55% of men was judged to be unacceptable.

•   Urinary changes  > 2 points are considered clinically significant.

o   Any such change affecting ≤ 40% of men was considered to be acceptable.

o   Any such change affecting ≥ 60% of men was considered to be unacceptable.

• Sexual score changes ≥ 11 points are considered clinically significant

After 1 year of follow-up, patient-reported clinically significant changes were noted in:

• Bowel changes were acceptable: 29.8% in Arm 1 and 28.4% in Arm 2
• Urinary changes were borderline acceptable: 45.7% in Arm 1 and 42.2% in Arm 2
• Sexual score changes: 32.9% in Arm 1 and 30.9% in Arm 2
• Disease-free survival at two years: 93.3% in Arm 1 and 88.3% in Arm 2
• None of the differences between Arm 1 and 2 were statistically significant

Physician-reported toxicities were as follows:

• Acute urinary: Grade 3 – 2 patients (1.7%)
• Acute rectal: Grade 3 – 2 patients (1.7%), Grade 4 – 1 patient (1.1%)
•  Late urinary: Grade 3 – 1 patient (0.8%)
•  Late rectal: Grade 3 – 2 patients (1.7%)

Both treatment regimens substantially met the study’s toxicity requirements, and confirm that 5 fractions are as toxicity-free as 12 fractions. These outcomes are in line with historical controls based on conventional IMRT treatment regimens. Of course, only a randomized clinical trial (like this one, which proved there were no differences in oncological or toxicity outcomes) can compare IMRT and SBRT.

EBRT works better with ADT for intermediate/high-risk prostate cancer

The EORTC trial 22991 compared EBRT + short-term ADT vs. EBRT alone in intermediate and high-risk men. The preliminary report by Bolla et al. was posted at the 2016 GU Conference. There are more details of the clinical trial available here. There were 819 patients in the European multi-institutional study:

• ·      407 received EBRT only, 403 received EBRT+6 months of ADT
• ·      Radiation dose: 70, 74, or 78 Gy (at discretion of each institution)
• ·      Pelvic node radiation: at discretion of each institution
• ·      75% intermediate risk, 25% high risk

After a median follow-up of 7.2 years,

• ·      5-year biochemical progression-free survival was 82.5% with the ADT, 69.3% without it.
• ·      Improvement was irrespective of radiation dose.
• ·      5-year clinical progression-free survival was improved by 7.9 percentage points.
• ·      Late urinary toxicity was 5.9% with the ADT, 3.6% without it (not statistically significant)
• ·      Severe sexual function impairment was 27.0% with the ADT, 19.4% without it (statistically significant)
• ·      Symptoms of hormone treatment, sexual activity and functioning were impaired at 6 months with ADT, but there was no difference at 2 years.

The authors conclude:

“The addition of 6 months of medical castration to primary irradiation improves BPFS and PFS in intermediate- and high-risk localized T1b-cT2a N0M0 prostatic carcinoma with no persistent detriment on HRQOL or sexual function.”

Unfortunately, this preliminary report doesn’t break out the intermediate and high-risk men separately.

We have previously looked at the DART 01/05 clinical trial that proved that at escalated radiation doses, long-term (28 months) androgen suppression improved cancer control better than short-term (4 months), at least for high-risk men. The benefit of longer duration ADT was not established for intermediate risk men at 5-year follow-up.

Nabid et al. focused on intermediate risk men and found a clear benefit to adding 6 months of ADT rather than none (after 10 years of follow-up).

It now seems clear that short-term androgen suppression improves results in intermediate risk men, while longer androgen suppression is necessary in high risk men. It would be helpful to know whether the improvement in intermediate risk men was only among the subgroup classified as “unfavorable intermediate risk.” ADT seems to have a more powerful effect than radiation dose, but it is unclear if that effect is maintained with therapies like SBRT and brachy boost that treat with much higher biologically effective doses. We are getting closer to defining an optimal duration of adjuvant ADT by risk level, and future trials using genetic classification data may provide better definition.