Sunday, August 28, 2016

SBRT for High Risk Prostate Cancer

Treatments for high risk prostate cancer are limited. Surgery is usually considered a poor option if the cancer has already escaped the prostate capsule (stage T3/4). External beam radiation is often given with hormone therapy for high grade cancers, or with a brachytherapy boost. Because of the radiological similarity between stereotactic body radiation therapy (SBRT) and high dose rate (HDR) brachytherapy, several radiation oncologists have wondered whether it can be used in a similar way.

Starting in 1996, HDR brachytherapy was used as a monotherapy for favorable risk prostate cancer. The early results were impressive. In 2003, Dr. Christopher King at Stanford first used SBRT (on a CyberKnife machine) to mimic HDR brachytherapy monotherapy in its use for prostate cancer. With brachytherapy, the X-rays travel from the inside out; with SBRT, they travel from the outside in. Dose per treatment and doses to the prostate and nearby organs at risk are very similar. Out of prudence, its use was initially restricted to favorable risk patients. Unsurprisingly, reported oncological and toxicological outcomes have been nearly identical between the two treatments.

For high risk patients, HDR brachytherapy has, since its early days, been used as a way of boosting the dose to the prostate while IMRT has been used to widen the treatment area. While there have been no randomized comparisons between IMRT monotherapy and IMRT with an HDR brachytherapy boost, Deutsch et al. at Memorial Sloan Kettering Cancer Center reported significantly better results in men treated with the brachytherapy boost than in men treated with IMRT alone, even at doses as high as 86 Gy. After five years of follow up, 93% of the high risk patients treated with the HDR brachytherapy boost were free of biochemical progression compared to 71% of the high risk patients treated with 86 Gy of IMRT alone.

It is tempting to look at the superior results reported for HDR brachytherapy boost therapy for high risk patients and wonder if that can be duplicated with SBRT alone. After all, SBRT can treat a wide margin around the prostate just as IMRT can, and it can be used at the same time to give a higher dose to the prostate itself. All of this could be done in five treatments instead of five weeks of IMRT, and without the anesthesia or hospital stay required for HDR brachytherapy. While SBRT promises increased convenience and lower cost, is it as effective and as low in toxicity?

The major differences between SBRT for high risk compared to favorable risk patients involve controversies about treatment margins, dose, use of androgen deprivation therapy (ADT) with it, and treatment of pelvic lymph nodes. Clinical trials have already started to explore these issues, and there is an SBRT registry that may provide some guidance eventually.

SBRT, as discussed in this article, is given with extreme hypofractionation only  – typically 6 Gy to 8 Gy per treatment in each of 5 treatments. There are several trials of more moderate hypofractionation, usually with 2.5 Gy per treatment.

There have been several pilot tests of IMRT with an SBRT boost to the prostate in high risk patients. Lin et al. reported on 41 patients. The 4-yr biochemical failure-free survival was 92%, with a mean PSA nadir of 0.05 ng/ml. Two of the 3 failures were distant metastases. No one suffered any Grade 3 or higher acute toxicity, and no one suffered any Grade 2 or higher late toxicity. Anwar et al. reported on 43 patients. The 5-yr biochemical control was 82%, with a mean PSA nadir of 0.1 ng/ml. None of the 4 failures were local.

Katz and Kang have published the largest and longest follow-up trial of SBRT for high risk patients, with 97 patients and 6 years of follow up. Of those, 45 were treated with an SBRT boost following whole pelvic IMRT radiation, and 52 were treated with SBRT monotherapy. The 6-yr biochemical disease-free survival was 69%. This did not differ significantly whether they received the SBRT boost or monotherapy. It also did not differ significantly whether they received adjuvant ADT. Several different doses were used, but none had significantly better performance. Higher stage and grade cancers were cured equally well. Only patients with high initial PSA, perhaps indicative of metastases, fared worse than patients with lower initial PSA. Late Grade 2 rectal toxicity was higher for the combo IMRT+SBRT treatment. Late urinary and rectal toxicity were low, and transient, with none after two years.  This was reflected in patient-reported quality-of-life scores, which declined immediately after treatment but returned to baseline in less than a year.

In a pooled consortium of 8 institutions and 1100 SBRT-treated patients, only 121 were high risk patients, and 97 of those were from Dr. Katz’s practice, and 16 were from Dr. Bolzicco’s practice (below). The 5-year biochemical recurrence-free survival for the high risk patients was 81%, so the 24 patients outside of Dr. Katz’s practice fared quite a bit better, but this simply reflects the more recent entries, mostly from Dr. Bolzicco’s practice. A recent study by Bernetich et al. included a small group of 18 high risk patients. Their 5-yr freedom from biochemical failure was 87%.  Bolzicco et al. treated 16 high risk patients as part of their SBRT clinical trial. After 3 years, only one (6%) had biochemically failed. Another small study by Oliai et al. included 12 high risk patients. Their 3-year freedom from biochemical failure was 77%. Two of the 3 patients who failed treatment had been given a lower radiation dose, and 2 of the 3 were diagnosed with distant metastases.

While the oncological control seems promising, and the toxicity is suitably low, there have not yet been enough high risk patients treated with SBRT to draw reliable conclusions. However, there are several single-institution clinical trials in progress:

·      Clinical Trial Number: NCT02296229
·      Lead Investigator: Dr. Christopher King
·      Institution: Jonsson Comprehensive Cancer Center, University of California Los Angeles
·      5 treatments, every other day
·      40 Gy to prostate, 25 Gy to pelvic lymph nodes (optional), 25 Gy to seminal vesicles (optional)
·      5 mm margin around prostate, 4 mm on rectal side
·      8 months of ADT starting 2 months before treatment (optional)
·      Goal: 5-year biochemical no evidence of disease – 85%
·      Enrollment: 220 patients
·      Study completion: November 2019
·      Status: enrolling patients

·      Clinical Trial Number: NCT01953055
·      Lead Investigator: Dr. Andrew Loblaw
·      Institution: Sunnybrook health Sciences Centre/University of Toronto
·      5 treatments over 4 weeks
·      40 Gy to prostate, 25 Gy to pelvic lymph nodes
·      3 mm margin around prostate, 6 mm margin around pelvic lymph nodes
·      Enrollment: 30 patients
·      Study completion: September 2019
·      Status: 30 patients, fully enrolled

·      Clinical Trial Number: NCT02229734
·      Lead investigator: Dr. Glenn Bauman
·      Institution: London Regional Cancer Program of the Lawson Health Research Institute
·      5 treatments over 5 weeks
·      35 Gy to prostate, no treatment of pelvic lymph nodes
·      18 months of ADT
·      Age > 70, or refusing other treatment
·      Enrollment: 60 patients
·      Study completion: November 2019
·      Status: enrolling patients

·      Clinical Trial Number: NCT01985828
·      Lead Investigator: Dr. Arica Hirsch
·      Institution: Advocate Lutheran General Hospital, Park Ridge, IL
·      50 Gy whole pelvic IMRT over 5 weeks + 21 Gy SBRT boost to the prostate in 3 treatments
·      6 months or 3 years of ADT
·      Enrollment: 72 patients
·      Study completion: December 2024
·      Status: enrolling patients

I encourage patients with a high risk diagnosis to consider enrollment in one of these trials.

Note: SBRT is sometimes known as Stereotactic Ablative Radiotherapy (SABR). SABR has a more euphonious abbreviation, and one suggestive of the sharp-edged precision also reflected in the brand names CyberKnife or GammaKnife. However, some find the knife imagery misleading, and the radiation, while ablative of the tumors within and around the prostate, is not ablative of the prostate itself.

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