Emerging Technologies in Prostate Cancer Radiation Therapy: Improving the Therapeutic Window

Matthew C. Biagioli, MD, MS; Sarah E. Hoffe, MD

Disclosures

Cancer Control. 2010;17(4):223-32. 

In This Article

Stereotactic Body Radiotherapy

Stereotactic radiosurgery is the delivery of a very high dose of radiation in a single treatment referred to as a fraction. This is essentially a form of ablative therapy. The first widely accepted clinical application of stereotactic radiosurgery was in the brain using the Gamma Knife system (Elekta AB, Stockholm, Sweden) and was developed by Lars Leksell, MD, at the Karolinska Institute. The Gamma Knife system uses 201 Cobalt-60 sources located in a ring around a central treatment point ("isocenter") and is capable of accuracies of greater than 1 millimeter. The Gamma Knife system requires a head frame bolted onto the skull of the patient and is capable of treating only cranial tumors. In order to prevent significant toxicity, radiosurgery can treat only small volumes of disease.

In the 1990s, technology advanced to allow the application of intracranial stereotactic techniques to body sites with the integration of strategies in order to define and minimize respiratory motion. With the advent of 4D CT scans, radiation oncologists had the ability to measure the motion of the tumor through all phases of a patient's breathing cycle. Body immobilization cradles were designed to keep the patient in the same position throughout treatment. These advances led investigators to begin pioneering SBRT, which is defined as the precise delivery of high-dose extracranial radiation in 1 to 5 treatment fractions. Timmerman et al[80] demonstrated that SBRT could be safely used in sites outside of the brain.

The concept of treating prostate cancer with higher doses per fraction over a shorter course is not new. Kupelian et al[81] reported on delivering 70 Gy in 2.5 Gy fractions using IMRT with acceptable toxicity. More interesting, for over 22 years beginning in 1962, Lloyd-Davies et al[82] described treating patients without the benefit of CT-based planning to a dose of 36 Gy in 6 fractions over 6 weeks. They demonstrated long-term safety and possible effectiveness, the latter being difficult to assess given the lack of modern staging and risk stratification. Regardless, this has generated a significant interest in SBRT for the treatment of low- to intermediate-risk prostate cancer, given the abbreviated treatment time without the invasiveness of brachytherapy.

To date, only two reports evaluating SBRT in prostate cancer are available. The first, from Madsen et al[83] at the Virginia Mason Medical Center, involved the treatment of 40 patients to a dose of 33.5 Gy at 6.7 Gy per fraction, equivalent to a standard dose of 78 Gy. They used a modified standard treatment machine with fiducial marker-based IGRT. With a median follow-up of 41 months, they reported biochemical freedom from relapse of 90% based on one definition of PSA failure. Late grade 2 and 3 GU and GI toxicity rates were 20% and 7.5%, respectively. King et al[84] from Stanford University recently published their initial results from a phase II trial evaluating 41 patients treated with the CyberKnife System (Accuray Inc, Sunnyvale, CA) to a dose of 36.25 Gy at 7.25 Gy per fraction, now with a median follow-up of 33 months. They reported no PSA failures, with 78% of patients achieving a PSA nadir of ≤ 4 ng/mL. Late grade 2 and 3 GU and GI toxicity rates were 29% and 15%, respectively, with no grade 3 GI toxicity. Using the International Prostate Symptom Score (IPSS) to assess GU toxicity and the Expanded Prostate Cancer Index Composite (EPIC) to assess GI toxicity, they noted GU and GI QOL scores of 2 or 3 (ie, small problem) to be 8% and 45%, respectively, and 9% for a GI QOL score of 4 (ie, moderate problem).

These initial SBRT results are promising, with excellent PSA control rates. However, given the need for 8- to 10-year follow-up with prostate cancer and the relatively small number of patients in these two studies, further investigation and longer follow-up are needed. Additionally, large doses per fraction have the propensity to result in late toxicity that may take years to arise and is suggested by the rate of over 50% small to moderate GI problems from the Stanford QOL assessments. For these reasons, prostate SBRT should not yet be considered a standard of care. Because of the increasing interest in prostate cancer SBRT without significant supportive evidence, the American Society for Therapeutic Radiology and Oncology recently released the following statement regarding its use:

" There is not sufficient or mature data to demonstrate equivalency to existing standard treatment modalities and, in our view, SBRT for prostate cancer patients does not represent a 'standard of care.' SBRT for early-stage, low-intermediate risk prostate cancer should be further tested within the context of appropriately designed clinical trials."

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