The “CYBERKNIFE” (Stereotactic Body Radiotherapy — SBRT): A Primer on a Promising Evolving Radiotherapy Treatment for Prostate Cancer
[This primer is largely based on the excellent review article by Robert Meier, MD, “Dose-escalated robotic SBRT for stage I-II prostate cancer,” Frontiers in Oncology, April 2015. Dr. Meier is a radiation oncologist at the Stereotactic Radiosurgery Center at Swedish Medical Center, Seattle, WA.]
What is the “CyberKnife?” “Stereotactic body radiotherapy (SBRT) is the precise external delivery of radiotherapy to targets in the body, with treatment completed in one to five fractions” (Meier). “CyberKnife” is the commercial name for this radiation delivery system that mounts a 6 MEV (million electron volt) source of radiation on an industrial robot. It delivers intense and sharply focused radiation to the target from a wide variety of angles.
How does CyberKnife treatment compare to standard Intensity Modulated Radiation Therapy (IMRT) as regards delivery of radiation doses?
Radiation dosage for CyberKnife systems is “hypo-fractionated” relative to standard IMRT technique, meaning that the total planned dose is delivered in fewer treatment sessions than with IMRT. For example, standard IMRT regimens usually deliver 2 Gy (a measure of radiation dose) per day for 39 days, impacting the prostate with a total of 78 Gy over 7-8 weeks. The CyberKnife program delivers five doses on consecutive days for a total dose up to 40 Gy. Radiation biology factors, however, stipulate that higher treatment fractions (i.e. 7-8 Gy per day) within a compressed delivery schedule results in a considerably greater total effective radiation (or biologic) dose to the prostate than standard IMRT, 100-109 Gy for SBRT (depending the chosen conversion factor) compared to 78 Gy for IMRT.
What is the biologic basic for “hypo-fractionation? The essential goal of fractionated radiation therapy is delivery of lethal therapy to the cancer while sparing the surrounding normal tissue from injury. Because prostate cancer, compared to most surrounding normal tissues, has a lower rate of proliferating cells, it is more sensitive to large doses per fraction, which at the same time should be less harmful to surrounding cells. However, since hypo-fractionated radiotherapy is relatively new, concern for the safely of nearby tissues has led researchers of hypo-fractionation to be especially focused on side effect issues relating to urinary, bowel, and erectile function.
Is hypo-fractionated radiotherapy for prostate cancer a very recent development? Hypo-fractionated radiotherapy is a relatively recent development. The first report of 5-year outcome was reported in 2007. Most mature clinical series of hypo-fractionated radiotherapy have follow-up intervals of usually 5-7 years and provide data about progression-free survival (PFS) and toxicity. But longer follow-up of (say) 10+ years will be necessary to obtain data about cancer-specific survival, late toxicity, and second malignancies.
How is the precision of targeting maintained during therapy? After initial target localization with CT, tiny gold “fiducial” markers are implanted into or around the prostate. These fiducial are detected by the orthogonal X-ray system built into the CyberKnife and inform the CyberKnife platform about target movement. The radiation is delivered with an accuracy of less than one millimeter. “With the Calypso system, the operator sets a threshold (typically 3-5 mm) beyond which the treatment is interrupted and the patient is repositioned. This monitoring occurs every 40 seconds during treatment.”
How effective is primary CyberKnife therapy? Katz et al., Journal of Medical Imaging and Radiation Oncology, 2014, reported PSA recurrence rates at 5 years (using the “Phoenix” standard metric of PSA nadir + 2 ng/mL) for 304 men. The results were 97%, 90.7%, and 74.1% for low-, intermediate-, and high-risk patients. A second study by Katz reported an actuarial 7-year PFS of 93.5% and 79.3% for low intermediate and high-high intermediate-risk men. Men in these risk categories are very appropriate for CyberKnife treatment. The outcome of these studies and many others compare favorably with the results of primary treatment with IMRT.
What are the rates of urinary, bowel, and erectile function toxicities from CyberKnife therapy? It is difficult to establish overall meaningful data about side effects since so many variables are involved. Side effects are graded in a conventional terminology in which Grade 1 and 2 represent mild to moderate difficulties, often transient. Grade 3 toxicity is more serious. In 2015 Dr. Meier et al. reported in abstract form the observations from a study of 137 men: “Acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities occurred in 23% and 9% of patients, respectively.” “Late (developing after 3 months) Grade 2 GU and GI toxicities occurred in 12% and 3% of patients, respectively. Two late Grade 3 GU toxicities were reported.”
“Physician-reported late urinary toxicity appears to be similar to external beam RT, and late GI toxicity appears to be less than with external beam and LDR brachytherapy (Meier).” One study found that of the 50% of men with functional erections prior to treatment, post treatment functional erections persisted in 38%, 35%, and 33% at 1, 2, and 3 years.
Current ongoing clinical trials will likely be informative as to comparative outcomes and toxicities. Four studies are comparing hypo-fractionated SBRT with convention IMRT as regards progression-free survival. One study compares prostatectomy to SBRT.
BOTTOM LINE: Dr. Meier concluded: “SBRT offers a cost-effective alternative to external beam radiotherapy which is more convenient for the patient.” “For low- and intermediate-risk prostate patients…, 5-year relapse-free survival rates are at least equivalent or possibly superior to conventionally fractionated RT.” However, until randomized studies are complete, comparison among modalities is incomplete.