THE "NEW" PROSTATE CANCER INFOLINK

This is the second part of a two-part commentary. In the first part, 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 low-dose-rate brachytherapy (the two most popular kinds of primary radiation) were local recurrences only (in the prostate and/or the seminal vesicles). In this part, we look at how SBRT is being used to treat such local recurrences.

Most of us have heard the oft-repeated aphorism from urologic surgeons: “If you choose radiation first, you can’t have surgery afterwards.” That is what Stephen Colbert would call “truthy.” Few surgeons are actually 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 in carefully selected patients (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 radiation therapy has been mostly limited to cryotherapy, although other kinds (like high-intensity focused ultrasound [HIFU] and laser ablation) may prove useful. Salvage radiation after first-line radiation therapy 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 dosing 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 dose of external beam radiation therapy : 73.5 Gy (range, 64.8 to 81 Gy)
  • 1 patient had received primary LDR brachytherapy, 1 had prior SBRT
• No lasting side effects  greater than grade 1 from the primary therapy
  • 48 percent had chronic grade 1 rectal or urinary side effects

At the time of salvage, the patient profile was:

• Median age: 73
• Stage at salvage:
  • T1c/T2a: 20 patients
  • T2b/T2c: 8 patients
  • T3: 1 patient
• Gleason score at salvage:
  • GS 6: 6 patients
  • GS 7: 12 patients
  • GS 8: 6 patients
  • 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
• 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 follow-up of 24 months:

• PSA decreased to 0.16 ng/ml
• 2-year biochemical disease-free survival was 82 percent
  • No local failures detected
  • No distant failures detected
• Among the 4 recurrences:
  • 3 were Gleason 6/7; 1 was Gleason 8/9
  • 2 were stage T1c; 2 were stage ≥ T2b
  • 3 had an original PSA ≤ 5.0; 1 had an original PSA > 10.0
  • 1 had prior ADT
• Late urinary toxicity:
  • Grade 2: 3 patients (10 percent)
  • Grade 3: 1 patient (3 percent) required catheter
  • Grade 4: 1 patient (3 percent) required cystoprostatectomy
  • The patient with prior LDR brachytherapy had severe urinary toxicity.
  • 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 percent) retained full potency.

Fuller is cautiously optimistic, noting the limited sample size and limited length of followup. 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.
• [¹¹C]Choline PET/CT was used in 88 percent to identify relapse.
• 47 percent 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 percent had adjuvant ADT
• Several treatment platforms were used
• Intra-fractional motion was tracked with fiducials.

After a median follow-up of 21 months:

• 5 percent had died
• 41 percent had no evidence of disease
• 47 percent had biochemical or clinical evidence of disease
• 38 percent had clinical progression
• 25 percent had out-of-field progression
• 5 percent had local progression

Among the 22 patients re-treated after primary radiation therapy:

• Grade 2 acute urinary toxicity: 2 patients (9 percent)
• 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 post-prostatectomy. On the other hand, toxicity was extremely low in this study.

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?

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.

Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: body, radiation, salvagee, SBRT, stereotactic |