CyberKnife Treatment of Prostate Cancer
Bentzen and Wasserman argue that “treating early-stage prostate cancer in ‘one to five outpatient sessions’ with the CyberKnife is unproven therapy ….” In addition to accusing CyberKnife clinicians of treating irresponsibly, this argument ignores the considerable data in support of a hypofractionated approach to prostate cancer treatment. First, it should be acknowledged that radiotherapy in general is a highly effective modality for treating prostate cancer. It is also well-established that greater radiation doses yield a greater rate of long-term freedom from recurrence and superior survival Hypofractionated CyberKnife treatment of the prostate is largely based on high-dose-rate (HDR) brachytherapy (a procedure not mentioned in the editorial by Bentzen and Wasserman). As with CyberKnife treatment, HDR brachytherapy has been used as monotherapy and to deliver a boost dose after external beam radiotherapy. Fairly long-term efficacy with minimal toxicity for HDR monotherapy has been established. Findings such as these, and an early publication that stated the rationale for using the CyberKnife to treat prostate cancer and established that treatment plans rivaling those used in intensity-modulated radiotherapy could be delivered using the CyberKnife encouraged its application for prostate cancer. Thus, CyberKnife clinicians made the initial decision to treat prostate cancer from a substantial body of published data—rather than embarking on an “unproven therapy,” they were simply using a different device to safely deliver radiation doses and fractions that had been proven safe and efficacious when delivered by another method.
The unique features of the CyberKnife System, and a growing body of published data that supports its broad application, also contribute to the confidence of clinicians in their ability to treat prostate cancer. The vast experience and clinical results treating intracranial targets with the CyberKnife gave clinicians confidence to use this frameless delivery system to treat extracranial targets. The CyberKnife System was approved by the Food and Drug Administration in 2001 for treatment of tumors anywhere in the body that radiotherapy is indicated. The system can deliver hundreds of uniquely angled radiation beams with extreme accuracy from a linear accelerator mounted on a robotic manipulator, making it ideal for treating extracranial targets in close proximity to critical structures. Its ability to continually track the target location with orthogonal X-rays taken frequently during a treatment fraction, and to automatically correct for any changes in target position, support its rapid adoption in applications such as spinal, lung, and pancreas cancer, despite the close proximity of critical structures to those targets. Bentzen and Wasserman would allow marketing based on a device's “superior operational characteristics,” but technical superiority and clinical confidence clearly go hand in hand. Thus, the first clinicians to treat the prostate with the CyberKnife were confident that they could generate rational hypofractionated treatment plans and, with continual, automatic image guidance, deliver them safely and noninvasively in a much shorter time than using conventional external beam radiotherapy.
In their article, Bentzen and Wasserman take Accuray to task because they could not locate published data that supported the claims in the press release. It is true that peer-reviewed data on use of the CyberKnife for prostate cancer treatment is sparse and the published follow-up is of short duration. Certainly, claims of long-term efficacy and safety cannot be made from the published data, and, indeed, no such claims were made in the press release. However, Bentzen and Wasserman state, “If Accuray has more clinical data than we could find, we would review it.” Therefore, we present data from studies, some of which include follow-up as long as 3 years, that were presented at meetings, the abstracts of which were peer reviewed.
Prostate cancer has been treated with the CyberKnife System under an institutional review board (IRB)–approved protocol at Stanford University since December 2003. Hara reported the early results from 26 low-risk prostate cancer patients with clinical Stage T1c-T2a, prostate-specific antigen (PSA) level <10 ng/mL, and Gleason score ≤7 at the 2006 meeting of the American Society for Therapeutic Radiology and Oncology. The patients were treated with 36.25 Gy delivered in five fractions within 5 days. The dose was delivered to 95% of the planning target volume, which was defined as the prostate with a 5-mm margin in all directions, except posteriorly, where it was reduced to 3 mm. At 18 months after treatment, the mean normalized PSA level had decreased to 0.22 ng/mL. Late bladder morbidity (Radiation Therapy Oncology Group scale) was reported as 73% Grade 0, 23% Grade 1, and 4% Grade 2. Late rectal morbidity was 65% Grade 0, 35% Grade 1, and 0% Grade 2. No patient developed late Grade 3 or 4 toxicity. Of course, the investigators concluded that long-term follow-up would be required to confirm the durability of the PSA reduction and assess for late toxicity. These data were updated in a presentation in January 2008 at the CyberKnife Users' Meeting (the CyberKnife Users' Meeting is held annually by the CyberKnife Society, an agency that is funded by Accuray Incorporated and by dues from members; abstracts are submitted to the Society and are reviewed and accepted or rejected by a board of CyberKnife User-peers who are not employed by Accuray Incorporated). King et al.described 41 low-risk, organ-confined prostate cancer patients treated with 36.25 Gy in five fractions. At a median follow-up of 30 months, they concluded, “within the limitations of this ongoing prospective trial we have demonstrated the safety and efficacy of hypofractionated stereotactic radiotherapy as monotherapy for low-risk prostate cancer.” Again, the investigators stated the need for additional long-term follow-up. A paper reporting this work is in preparation.
At the 2007 CyberKnife Users' Meeting, Freeman reported the results from the first 40 patients with low-risk, organ-confined, prostate cancer treated at Naples Community Hospital (Naples, FL). Patients with clinical Stage T1c, PSA level <10 ng/mL, and Gleason score ≤7 were treated with 35 Gy in five fractions under an IRB–approved protocol. The mean PSA level before CyberKnife treatment was 5.78 ng/mL. At 1 year after treatment, the mean PSA level was 1.2 ng/mL in the 27 patients who had not received hormonal therapy and 0.05 ng/mL in the patients who had. The acute side effects included urinary urgency and frequency, tenesmus, loose stools, and fatigue in the first 5–10 days after treatment. No Grade 4 toxicities were reported. At the 2008 CyberKnife Users' Meeting, Friedland described their ongoing experience at Naples Community Hospital with 181 patients with low- and intermediate-risk prostate cancer treated with CyberKnife monotherapy under an IRB–approved protocol. They reported an excellent PSA response at 2 years after treatment, with most patients regaining baseline urinary, bowel, and erectile function within 1 month of treatment. A paper reporting this work is in preparation.
At the 2007 American Society for Therapeutic Radiology and Oncology meeting, Choi reported the results from 44 prostate cancer patients treated with the CyberKnife at the Korea Institute of Radiological and Medical Sciences. This was a follow-up to a study presented at the 2006 American Urological Association meeting. Ten patients with low-risk (PSA level <10 ng/mL, Gleason score ≤6, Stage T1b-T2a), 25 patients with high-risk (PSA level >20 ng/mL or Gleason score ≥8), and 9 patients with intermediate-risk (defined as other than low or high) localized prostate cancer were treated with the CyberKnife as monotherapy. All but 1 patient was treated with 32–36 Gy in four fractions. One patient was treated with 24 Gy in three fractions. At a median follow-up of 13 months (range, 4–46), the 3-year biochemical disease-free survival rate was 78.3% and the 3-year overall survival rate was 100%. Four patients experienced biochemical failure. Of the 44 patients, 14 experienced Radiation Therapy Oncology Group Grade 1 and 2 rectal toxicity and 17 reported Radiation Therapy Oncology Group Grade 1 and 2 urinary toxicity. No Grade 3 or greater rectal or urinary toxicity was reported. The investigators concluded that CyberKnife monotherapy yielded acceptable efficacy and short-term toxicity for localized prostate cancer.
Early clinical observations of 10 localized prostate cancer patients treated with the CyberKnife using a HDR-like dose distribution were presented at the 2007 American Society for Therapeutic Radiology and Oncology annual meeting. The data were recently published by Fuller The IRB-approved study sought to determine whether the CyberKnife could create and deliver treatment plans with a dose distribution that approximated those delivered by HDR brachytherapy. Patients were treated with 38 Gy in four fractions. For each patient, a simulated HDR plan was designed using 15–20 simulated HDR catheters to match the CyberKnife dosimetry. The CyberKnife plans did, indeed, approximate the HDR dosimetry within the planning target volume and consistently resulted in lower radiation exposure to the urethra, suggesting that patients treated with the CyberKnife stereotactic radiosurgery system would have decreased urethral toxicity compared with patients treated with HDR brachytherapy. The preliminary clinical results demonstrated an 86% reduction in the PSA value at 6 months after treatment, with minimal toxicity. Again, longer follow-up is needed to assess the long-term efficacy and safety of HDR-like dosimetry using the CyberKnife System for localized prostate cancer.
With the resources of the CyberKnife Society, interested CyberKnife users have met frequently during the past several years to develop protocols for a number of emerging CyberKnife applications. The CyberKnife community has always displayed caution when planning new treatments. The caution is reflected in the painstaking work of the CyberKnife Society Protocol Development Committee, under the direction of Dr. Robert Meier of the Swedish Cancer Center in Seattle and Dr. Irving Kaplan from Beth Israel in Boston. In addition to describing specific patient selection criteria and treatment parameters, the final prostate cancer protocols require patients to be counseled regarding the pros and cons of CyberKnife treatment, the clinical findings to date are discussed, and the lack of long-term efficacy and toxicity data is stressed.
Accuray is sponsoring two multi-institutional Phase II studies to collect long-term data on tumor control, biochemical disease-free survival, overall survival, and cancer-specific survival in low- and intermediate-risk prostate cancer patients treated with the CyberKnife System. One, led by Dr. Robert Meier, involves 18 centers nationwide, including academic institutions, community hospitals, and free-standing CyberKnife centers. Each center has received IRB approval for participation in the study. The study will also assess acute and late gastrointestinal, genitourinary, and sexual function toxicities and quality-of-life indexes for 5 years after CyberKnife treatment. Low-risk patients include those with clinical Stage T1b-T2a, PSA level <10 ng/mL, and Gleason score ≤6; intermediate-risk patients include those with clinical Stage T1b-T2b, PSA level of 10–20 ng/mL, or Gleason score 7. Patients will be treated with 40 Gy delivered to the prostate and 36.25 Gy delivered to the planning target volume in five fractions. The study will enroll 298 patients and is expected to reach accrual within 18–24 months.
The second clinical study is being led by Dr. Donald Fuller of the San Diego CyberKnife Centers. In that study, early-stage, low- and intermediate-risk prostate cancer patients will be treated with 38 Gy in four fractions delivered in an HDR-like treatment plan. This differs from the previous protocol, in which a more homogeneous dose distribution will be delivered. In the second study, the dose will be prescribed to the <66% isodose line, with the goal of delivering approximately 150% of the prescription dose to the periphery of the prostate. It is in the peripheral zone that most prostate cancer cells have been reported to reside. Again, acute and late toxicity, biochemical disease-free survival, overall survival, and cancer-specific survival will be assessed during the 5 years after treatment. This study will enroll 253 patients and currently involves seven CyberKnife centers nationwide.
The goals of this rebuttal were to outline some of the evidence that guided the initial decisions to use the CyberKnife System to treat prostate cancer, describe ongoing research, publicized in meetings and in print, on CyberKnife treatment of prostate cancer, and to indicate the commitment of Accuray and the CyberKnife community to the responsible development of prostate cancer protocols and clinical studies. We hope that this brief review has provided the context for Accuray's decision to release to the press the September 2007 piece marking the 1,000th prostate cancer patient treated with the CyberKnife System. The intent of the press release was only to give potential customers and investors a sense of the growing confidence of the CyberKnife community that they are able to deliver high-dose, hypofractionated radiotherapy to the prostate using a method that has led to excellent, albeit short-term, clinical outcomes, and does so, most importantly, without causing the patient serious injury.