Sunday, August 28, 2016

The multi-factorial nature of SBRT safety

In a previous article, we looked at the experimental use of extreme hypofractionated radiation therapy, SBRT or SABR, to treat high-risk patients. Here, we take a closer look at an early safety study by Bauman et al. that shows why radiation safety is more complicated than just setting the treatment dose.

Bauman et al. treated 15 high-risk men who were either frail and elderly, or who refused a long course of IMRT. They were all given 12 months of ADT beginning 2 months before SBRT.

After 6 months of follow up, the following rates of genitourinary (GU) and gastrointestinal (GI) toxicity were observed:
  • ·      Acute GU toxicity: Grade 2: 27%, none higher
  • ·      Acute GI toxicity: no Grade 2 or higher
  • ·      Late-term GU toxicity: Grade 2: 33%, Grade 3: 7%
  • ·      Late-term GI toxicity: Grade 2: 27%, Grade 3: 20%, Grade 4: 7%
  • ·      Toxicity was not correlated with patient frailty

All of the toxicities were higher than expected, and the high rates of high-grade late-term GI toxicity were particularly troubling. As a result, the treatment plans have been altered. They eliminated the dose to the pelvic lymph nodes entirely, extended the ADT treatment to 18 months, and reduced the dose to the prostate to 35 Gy across 5 treatments, with only one treatment per week. This is similar to the plan that Dr.Katz has been using for his high risk patients with 6 years of reported follow up with very low rates of toxicity (see Katz and Kang 2014).

Dr. King has been using the same prostate dose that Dr. Bauman used -- 40 Gy across 5 treatments (NCT02296229). Dr. King has used this dose for all his patients (not just high-risk ones) since 2008 with low rates of toxicity, and he is now treating pelvic lymph nodes on select high-risk patients with 25 Gy. Both King and Bauman use an arc radiation therapy machine, although the brands they use differ – Varian and Elekta, respectively. So what accounts for the very different toxicity outcomes they are getting? Let’s look a little closer.

The following table highlights key dosimetric differences between King and Bauman’s high-risk SBRT protocols.

Prescribed dose to prostate
40 Gy (8 Gy x 5)
40 Gy (8 Gy x 5)
Margin treated
5 mm all around
5 mm, except 4 mm posterior
Prescribed dose to SV
40 Gy (8 Gy x 5) in first cm of SV
25 Gy (5 Gy x 5) to entire SV

Margin treated
5 mm
No margin
Pelvic lymph nodes
25 Gy (5 Gy x 5)
25 Gy (5 Gy  x 5)
Margin treated
5 mm
Bladder dose constraints:
≤50% receives >29 Gy
≤30% receives >35 Gy
<10 cc receives >25 Gy
Max. point dose= 40 Gy
Rectal dose constraints:
≤50% receives >27 Gy
≤20% receives >35 Gy
<5 cc receives >25 Gy
Max. point dose= 42 Gy
(additional specific constraints for each side of the rectal wall)
Small bowel dose constraints:
<2 cc receives >27.5 Gy
<190 cc receives >25 Gy
<10 cc receives >20 Gy
Max. point dose= 25 Gy
Imaging for planning
CT/MRI fused images
Inter-fractional motion tracking
Cone beam CT
Cone beam CT with fiducials
Intra-fractional motion tracking
Stereoscopic X-rays. Fiducials were realigned every half-arc, approximately 40 seconds.

In comparing the treatment parameters of the two plans, we begin to see why the original Bauman plan would have greater toxicity in spite of the fact that the prescribed dose to the prostate was the same. Perhaps the single biggest drawback to the Bauman plan was the lack of tracking of intra-fractional motion. The prostate can move quite a bit during the treatment. With the low doses of IMRT (1.8-2.0 Gy each) it would not matter so much, but with the higher SBRT doses (8 Gy each), significant amounts of radiation may inadvertently hit the bladder and rectum if the motion is not controlled for.

The other advantages of the King plan include:
  • ·      Smaller margins where the prostate abuts the rectum
  • ·      No margins around the pelvic lymph nodes that could impact the small bowel
  • ·      No margins around the seminal vesicles that might hit the bladder neck
  • ·      Tighter bladder and rectal dose constraints
  • ·      MRI for more precise planning
  • ·      Fiducials for more precise image alignment
  • ·      Alignment is frequent and automatic. It’s not dependent on human intervention.
  • ·      Optional selection of patients suitable for nodal radiation (e.g., no anatomic abnormalities, presence of visceral fat, high risk of nodal involvement)
  • ·      Only 9 months of optional ADT are used

Dr. King has so far treated 19 high-risk patients on his protocol, 10 with nodal radiation. So far there have been no Grade 3 or higher toxicities of any kind. King uses Varian’s Truebeam with RapidArc and realigns four times during each fraction. The total treatment time is about 5-10 minutes each, with hundreds of beams emitted during each 40 second arc. Accuray’s CyberKnife, the most prevalent platform for SBRT, realigns the beams with the fiducials every few beams, and there are hundreds of beams. That extends the treatment time to about an hour each. While many different brands of linear accelerator platforms and image-guidance systems can be used for SBRT, it is vital that continual motion tracking or prostate stabilization (e.g., using a rectal balloon) be incorporated.

Other clinicians have sought the optimal SBRT treatment dose while all the other treatment parameters are held constant. Katz et al. (2011) tried two different doses, 36.5 Gy and 35 Gy, and found the lower dose had similar oncological results. While urinary toxicity was lower for the lower dose in a matched pairs analysis, the difference was not statistically significant. In contrast to Katz,  Bernetich et al.  found that there was a better oncological response to higher doses (37.5 Gy) for higher risk patients, but they also observed an increase in persistent GU toxicity, while GI toxicity remained low and unaffected by dose.  In a study that I consider to be of questionable ethics, Kim et al. experimented with SBRT doses as high as 50 Gy to find the SBRT dose limit for rectal tolerance, and not unexpectedly, found very high amounts of rectal toxicity associated with it. Currently, Dr. Zelefsky is the lead investigator on clinical trial at Memorial Sloan Kettering Cancer Center where he is raising the dose incrementally in successive cohorts of low and intermediate risk patients after insuring the safety of each lower dose. He has so far raised the SBRT treatment dose as high as 45 Gy. Clearly, there are many factors that affect SBRT toxicity, and there are still many details to be learned about SBRT dosimetry.

 note: Thanks to Dr. King for supplying the details of his protocol for high-risk patients and his update so far.

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