CyberKnife Monotherapy for Prostate Cancer

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1 C H A P T E R 29 CyberKnife Monotherapy for Prostate Cancer Clinton A. Medbery Marianne M. Young Astrid E. Morrison J. Stephen Archer Maximian F. D Souza Cindy Parry Abstract The purpose of our planned phase 1 study is to determine the feasibility and acute toxicity of delivering extracranial stereotactic radiosurgery as definitive therapy for early stage localized prostate cancer. Patients with adenocarcinoma of the prostate of stages T1-T2a, Gleason score < 6 with < 33% of core involvement and serum PSA < 10 are enrolled in our study. They receive, over a period of seven days, 38 Gy in four fractions of CyberKnife radiosurgery. The urethral dose is limited to less than 115% of the prescribed dose. Acute urinary and gastrointestinal toxicity are scored according to the Common Terminology Criteria for Adverse Events. Response to treatment is determined by physical examination and serum PSA levels. Our pilot trial plans to enroll 10 patients and to date three patients have been treated thus far with no grade 3 or higher toxicities observed. It is feasible both technically and clinically, to deliver CyberKnife stereotactic radiosurgery as a definitive therapy to patients with localized, early prostate cancer in a non-university community hospital setting. We report on the potential advantages of CyberKnife treatment and our procedures for treatment planning and treatment delivery. Introduction For many years, radical prostatectomy and traditional external beam radiation therapy remained the mainstays of treatment for prostate cancer. However, by the early 1970s, brachytherapy using an open technique had entered use in a few facilities 1. Then within a decade, open technique brachytherapy had been 325

2 3 2 6 PA RT I V: Non-Central Nervous System Applications supplanted by an ultrasound-guided transperineal approach, first in Europe 2 but soon also in the United States. 3 Both open and transperineal low dose rate (LDR) brachytherapy 125 Iodine seed implants involve potentially significant radiation exposure to medical personnel and families of patients. There are also dosimetric problems inherent in placement of seeds of uniform strength whose exact post-implant location cannot be precisely predicted. These problems, combined with a growing appreciation of the unique radiation biology of prostate cancer, led Martinez to begin trials of high dose rate (HDR) brachytherapy, both as a boost during or after external beam radiation 4 and as monotherapy. 5 Our current studies of CyberKnife monotherapy are based, with appreciation and respect, on the work of Dr. Alvaro Martinez of William Beaumont Hospital, Royal Oak, Michigan. Radiobiology of Prostate Cancer The linear-quadratic formula has become the most common model for describing the effects of radiation fraction size on both tumors and normal tissues. Although a complete explanation of the linear-quadratic model is beyond the scope of this discussion, a knowledge of the basic concepts is essential to understanding the rationale for CyberKnife monotherapy. Simply put, the α/β ratio is that dose at which single-hit and multi-hit mechanisms are equally important in cell-killing. Most tumors and mucosal surfaces have an α/β ratio of about 10 Gy, indicating a greater sensitivity to multi-hit killing. This means that they will respond most completely to repeated small doses of radiation. Most normal tissues are late-responding tissues that have low α/β ratios, indicating a greater sensitivity to single-hit killing. These will be most effectively treated (or harmed) by a smaller number of larger fraction sizes. Prostate cancer is virtually unique among cancers in having an α/β ratio that is as low as, or lower than, the ratios for late-responding tissues. Several investigations have consistently shown a low α/β ratio for prostate cancer, and these have variously estimated the ratio at Gy. 6 8 This compares to values of 3 4 Gy for many late-responding normal tissues. This unique radiobiological characteristic of prostate cancer implies not only that prostate cancer may be cured with large fraction sizes, but also that the negative impact on local normal tissues may be reduced with such a fractionation schedule. 9 Potential Advantages of CyberKnife Treatment The CyberKnife consists of two main components: an X-band linear accelerator on a highly precise robotic arm, and an orthogonal imaging system. The lightweight linear accelerator moves in space on the surface of a large spherical volume. This greatly increases the solid angle for treatment relative to traditional linear accelerator systems. It is thus possible to devise plans that maximally avoid treatment of organs at risk. The imaging system uses either bony anatomy (for treatment of lesions within or near the cranium) or implanted fiducials to track tumor movement. It allows positional checking and correction on as frequent a basis as the user desires, thus assuring accurate treatment. Data from Chang et al 10 and Yu et al 11 for the CyberKnife reported start-of-scan to endof-treatment accuracy of about 1 mm in head and body radiosurgery. This degree of accuracy, combined with the continuous imaging, anatomical checking and, re-registration throughout the procedure, makes extracranial stereotactic treatment possible, without the requirement for rigid immobilization. Initial experience suggests that we can treat with lower urethral doses than achieved with brachyther-

3 C H A PTER 29: CyberKnife Monotherapy for Prostate Cancer 327 apy. In addition it appears that shaping of the volume spares the higher doses and may allow treatment without regard to previous transurethral resection of the prostate (TURP) provided that the defect is of a manageable size. Median lobes are also less problematic than with brachytherapy. CyberKnife Treatment Planning The key to accurate treatment is to have good fiducial placement and accurate, reproducible imaging and patient positioning. At our institution, we are treating all monotherapy patients on an investigational protocol. As part of that protocol, we acquire a prostate volume prior to approval for treatment, requiring a volume of 80 cc or less. For patient comfort, we perform the volume study under conscious sedation. We insert a red Robinson or Foley catheter into the urethra and fill it with aerated lubricant jelly. Serial images are then obtained from base to apex using a standard prostate brachytherapy ultrasound set-up. Provided the volume is 80 cc or less, we proceed immediately to fiducial placement. Two needles are loaded with gold fiducial markers with variably loaded spacers. The brachytherapy grid and ultrasound analog are then used to insert spinal needles at eccentric locations in the prostate to provide local anesthesia. The fiducial seeds are then deposited in the same anesthetized locations. We usually place two seeds in the anterior right, two in the lateral mid-left gland, and two posteriorly on the right. This has always given us sufficient separation of the seeds for good positional calculations and tracking. Several days are allowed to elapse after seed placement to permit any minor migration of seeds to occur. The patient is prepped for high resolution CT scanning with 100 cc of quarter-strength contrast is instilled into the bladder through a Foley catheter that is left in place for the initial scan. Dilute barium Table 1. Representative treatment planning doses. Organ Minimum dose (Gy) Maximum dose (Gy) Prostate Bladder Urethra 35 Rectum 33 Figure 1. Dose-volume histogram (DVH) plots for the urethra and the prostate in a typical treatment for prostate cancer.

4 3 2 8 PA RT I V: Non-Central Nervous System Applications Figure 2. Isodose distribution for a typical prostate cancer CyberKnife treatment. may be placed into the rectum using a red Robinson catheter. Images are obtained at mm slice thickness from above the bladder to below the ischial tuberosities. The Foley catheter is then withdrawn into the urethra and a few ml of contrast are injected into the urethra to perform a urethrogram. This gives good visualization of the prostatic apex, which will later allow avoidance of the penile bulb, thought to be important for maintenance of potency. A more limited scan from the base of the prostate to below the prostate apex is then obtained using the same technical specifications as the previous scan. Care is taken to avoid putting any traction on the catheter so that there is no deformation of the prostate. Images are transferred to the CyberKnife treatment planning system (TPS) and the two CTs are then fused. The large scan is the one actually used for planning, but the fusion image allows accurate placement of the apex. Complete contours of the prostate and

5 C H A PTER 29: CyberKnife Monotherapy for Prostate Cancer 329 Figure 3. Isodose distribution for a high dose rate (HDR) brachytherapy treatment. bladder are entered. The urethra is contoured from the bladder to at least 2 3 cm below the apex of the prostate. The rectum is contoured from the verge to about the top of the bladder. If visualized on CT, the neurovascular bundles are contoured, although these are not consistently visible on the CT scans. The CyberKnife TPS is then employed to derive a treatment plan, using inverse planning. The 20 mm collimator is usually preferred. Marginally better plans can sometimes be obtained with the 15 mm collimator, but at a cost of 30 or more extra minutes of treatment time per day. Although every plan is somewhat different, the doses in Table 1 represent a good starting point for planning. In our experience, it has always been possible to obtain coverage of greater than 99% of the prostate with the 75% isodose line, see Figure 1. This procedure avoids, the extremely high urethral doses typical of HDR brachytherapy catheters. Figure 2 and Figure 3 give a comparison of isodose distri-

6 3 3 0 PA RT I V: Non-Central Nervous System Applications butions for the CyberKnife and for HDR 192 Iridium brachytherapy. CyberKnife Treatment Delivery Treatment can present significant challenges. In order to maintain the same anatomy as at the time of the CT scans, we daily insert a Foley catheter. Use of intraurethral lidocaine jelly minimizes discomfort. Changes in filling of the rectum and bladder, particularly the rectum, can change the position of the prostate. Although this can sometimes result in translational changes (x, y, z coordinates), more frequently it results in rotational dislocations, particularly in the head-up/head-down (pitch) dimension. Any rectal spasm causes similar dislocations. When it becomes available, we will be investigating the use of a conformal rectal balloon (basically an endorectal MRI balloon and probe without the electronics) for prostate immobilization to reduce set-up times. Treatment times can be rather lengthy. A typical plan may require about 90, ,000 monitor units. The CyberKnife currently delivers 400 monitor units per minute, and for set-up, robot movements and changes between paths require about 40% additional time. This means that daily treatment times are about 90 minutes and may be longer if there is significant prostatic movement. Future Advances The immediate future for CyberKnife treatment of prostate cancer will probably revolve around improving our current treatment philosophy and collecting data that show that CyberKnife treatment is safe and effective. If the dose rate from the linear accelerator is increased, it may be feasible to use smaller collimators, thus increasing urethral sparing. Several centers are now treating with essentially the same protocol that we use, and Stanford has an independent protocol already underway. These trials should give us good data on acute toxicity and patient tolerance within 1 2 years. Obviously, collection of information on efficacy of treatment and late complications will require several more years. Use of a conformal endorectal balloon will permit better immobilization of the prostate. Also if a true endorectal MRI coil is used, the potential then exists for several enhancements in treatment. Firstly, the MRI may allow greater sparing of vascular structures important in the preservation of potency. 12 Another intriguing possibility is the use of the MRI to define high-risk areas for a boost treatment. 13 Because of the nature of the CyberKnife planning and treatment system, this boost could occur as part of the same four day treatment regimen. References 1. Whitmore WF, Hilaris B, Grabstald H. Retropubic implantation of 125 Iodine in the treatment of prostatic cancer. J Urol 1972;108: Holm HH, Juul N, Pedersen JF et al. Transperineal 125 I seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983;130: Blasko JC, Ragde H, Schumacher D. Transperineal percutaneous 125 Iodine implantation for prostatic carcinoma using transrectal ultrasound and template guidance. Endocuriether Hypertherm Oncol 1987;3: Martinez AA, Kestin LL, Stromberg JS et al. Interim report of image-guided conformal high dose rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II dose escalating trial. Int J Radiat Oncol Biol Phys 2000;47: Martinez AA, Pataki I, Edmundson G et al. Phase II prospective study of the use of conformal high dose rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: a feasibility report. Int J Radiat Oncol Biol Phys 2001;49:61 69.

7 C H A PTER 29: CyberKnife Monotherapy for Prostate Cancer Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999;43: King CT, Fowler JF. A simple analytic derivation suggests that prostate cancer α/β ratio is low. Int J Radiat Oncol Biol Phys 2001;51: Fowler JF, Chappell RJ, Ritter MA. Is the α/β ratio for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001;50: Fowler JF, Ritter MA, Chappell RJ et al. What hypofractionated protocols should be tested for prostate cancer? Int J Radiat Oncol Biol Phys 2003;56: Yu C, Main W, Taylor D et al. An anthropomorphic phantom study of the accuracy of CyberKnife spinal radiosurgery. Neurosurgery 2004;55: McLaughlin PW, Narayana V, Meriowitz A et al. Vessel-sparing prostate radiotherapy: dose limitation to critical erectile vascular structures (internal pudendal artery and corpus cavernosum) defined by MR imaging. Int J Radiat Oncol Biol Phys 2005;61: Pickett B, Vigneault E, Kurhanewicz J et al. Static field intensity modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3D radiotherapy. Int J Radiat Oncol Biol Phys 1999;43: Chang SD, Main W, Martin DP et al. An analysis of the accuracy of the CyberKnife: a robotic frameless stereotactic radiosurgical system. Neurosurgery 2003;52:

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