Safety limits of SBRT dose escalation

In a recent commentary, we saw that the lack of a standard of care for stereotactic body radiation therapy (SBRT) dose escalation may put patients at risk when dose limits are pushed beyond what is customarily considered effective and safe. Hannan et al. have now published their efficacy findings. Further details of the IRB-approved clinical trial specs are available here.

Between 2006 and 2011, the researchers at several institutions conducted a dose escalation trial utilizing SBRT on 91 men treated for low- and intermediate-risk prostate cancer. Among those men:

  • 64 percent were intermediate risk, defined as
    • Either Gleason score 6 and PSA between 10 and 20 ng/ml
    • Or Gleason score 7 with PSA ≤ 15 ng/ml and clinical stage ≤ T2b
  • 36 percent were low risk by the NCCN definition

All patients received 5 treatments or fractions. The first 15 patients were treated with 45 Gy, the next 15 with 47.5 Gy, the next 15 with 50 Gy. Because that last group did not exhibit their predefined “maximally tolerated dose” in the short term, an additional 47 patients also received the 50 Gy dose.

The cancer control was excellent. At 5 years after treatment:

  • 98.6 percent were free from biochemical failure.
  • 100 percent were free from metastases.
  • None had died of prostate cancer.
  • Overall survival was 89.7 percent

Toxicity was another matter.

There were no reports of serious acute urinary toxicity. However, late-term urinary toxicity of grade 3 or greater was reported in 5.5 percent of patients. For the purposes of their analysis, acute toxicities were those observed within 9 months of treatment, and late-term toxicities were those observed between 9 and 18 months.

Rectal toxicity was reported in detail earlier (by Kim et al.) and merits a closer look:

  • Among those who received 45 Gy there was
    • No serious (grade 3 or higher) acute or late-term toxicity
    • No acute grade 2 toxicity
    • Late-term grade 2 toxicity in 1/15 patients (7 percent)
  • Among those who received 47.5 Gy there was
    • No serious (grade 3 or higher) acute or late-term toxicity
    • Acute grade 2 toxicity in 4/15 patients (27 percent)
    • Late-term grade 2 toxicity in 5/15 patients (33 percent)
  • Among the 61 patients who received 50 Gy there was
    • 1 case of life-threatening (grade 4) acute toxicity
    • 1 case of serious (grade 3) acute toxicity
    • 2 cases (3 percent) of life-threatening (grade 4) late-term toxicity
    • 3 cases (5 percent) of serious (grade 3) late-term toxicity
    • 2 of the patients developed rectourethral fistulae, and 5 required diverting colostomies.

We note that even at the lowest dose level given in this trial (45 Gy), they were delivering much more than the customary SBRT dose of 36.25 Gy. Because this study began with such a high dose, it did not succeed in its objective of finding an optimal dose. It did, however, find the dose that created dose-limiting toxicity. At 50 Gy, they were delivering a dose that is bioequivalent to more than twice the customary and safe dose of intensity-modulated radiation therapy or IMRT (80 Gy in 40 fractions). This is especially troubling when we realize that 36 percent of the patients were low-risk patients who might have delayed treatment with active surveillance.

There are many aspects of this study that are hard to understand. It’s hard to understand why they didn’t start at a more reasonable dose level. Katz and Kang reported excellent cancer control with extremely low toxicity using only 35 Gy (see this link). With the sharp increase in acute grade 2 toxicities at 47.5 Gy, it’s hard to understand why the researchers did not pull the plug before patients were seriously harmed. It’s also hard to understand how the internal review board (IRB) did not question the ethics of this study.

We have observed previously (see this link) that there is a lot more to SBRT safety than simply setting the prescribed dose. Careful planning, image guidance, and accurate delivery are equally important. In the right hands, SBRT is among the safest and most effective of all radiation therapies, with excellent convenience and relatively low cost. In fact, I chose it for myself.

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

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