Stereotactic Body Radiation Therapy for Localized ...

Stereotactic Body Radiation Therapy for Localized Prostate Cancer N I CH O L AS G. Z AO RSK Y Robert B. D en J J OV E RV I E W This chapter discusses the use of stereotactic body radiation therapy (SBRT) for the treatment of localized prostate cancer. Since 2001, SBRT has been touted as a superior type of external beam radiation therapy (EBRT) for the treatment of various tumors. SBRT developed from the theory that high doses of radiation from high-dose rate brachytherapy (HDR-BT) implants could be recapitulated from radiation treatment planning and delivery systems. In addition, SBRT has been theorized to be advantageous compared with other radiation therapy (RT) techniques in terms of radiobiology, radiophysics, patient convenience, and resource allocation. In this chapter, we discuss the impetus behind SBRT and the clinical evidence supporting its use for prostate cancer. As of 2013, studies of SBRT provide encouraging results of biochemical control and late toxicity rates. However, they are limited by a number of factors; these include short follow-up, exclusion of intermediate- and high-risk patients, and relatively small number of patients treated.

J J BAC KG RO U N D A N D H ISTO RY O F I N C R E A S I N G D OS E PE R FR AC TI O N Given the widespread use of prostate-specific antigen testing, most prostate cancer patients present with localized disease (clinical stage T1–T2). Treatment options for localized disease include radical prostatectomy (RP) and RT. RT is delivered as either a BT or an EBRT. Currently, most men who receive EBRT are treated with conventionally fractionated radiation therapy (CFRT; a single 1.8–2.0 Gy fraction lasting 15 minutes per day, 5 days per week, for about 8 weeks) to a total dose of 76 to 80 Gy. In the mid-1990s, the most commonly used method to deliver CFRT was a four-field technique. At that time, there was no consistent agreement on the optimal schedule 18 8

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or dose used for patient treatment (1). CFRT schedules were typically administered over 6 to 7 weeks with doses of 60 to 70 Gy (2). Dose-escalated CFRT (i.e., using the same dose per fraction, but up to ~80 Gy, for 8–9 weeks) was shown in multiple phase III randomized controlled trials to improve biochemical control rates and became the standard of care EBRT schedule (3–7). In 2001, hypothesis-generating reports suggested that prostate cancer had a low α/β ratio of ~1.5 Gy (8), implying that those cells were more sensitive to doses delivered in larger fraction size. Given the lower α/β ratio for prostate cancer than bladder and rectal mucosa (where the most late toxicity occurs), reduced morbidity was expected from hypofractionated radiation therapy (HFRT; 2.1–3.5 Gy/fraction, 5 days per week, for about 4 weeks) (9). Although there has been controversy in calculating the accurate α/β ratio for prostate cancer (10), prospective phase III superiority studies using HFRT (11–19) have been published based on the assumption that the α/β ratio for prostate cancer is 1.5 Gy. The results of these studies have been inconclusive (20). The older studies (11–13) reached opposite conclusions about HFRT compared with CFRT and differed greatly in their methodology from the modern studies. The more modern studies comparing HFRT with CFRT (14–18) have not shown a clear reduction in the incidence of late complications while maintaining biochemical control rates. There has been interest in increasing fraction size even further than 3.5 Gy/fraction to provide for tumor control, decrease toxicity, and reduce overall treatment time. SBRT (a single 3.5–15.0 Gy fraction lasting 1 hour per day, 5 days per week, for about 2 weeks), also called extreme hypofractionation, was shown to recapitulate HDR-BT plans closely and deliver such doses noninvasively (21). Use of SBRT increased in the 2000s due to the advent of image-guided technologies that improved the accuracy of delivering high doses of radiation. Moreover, SBRT has been theorized to have advantages (1) from a radiobiological perspective; (2) in treatment delivery from a radiophysics perspective; (3) to the patient himself, compared with other treatment modalities; and (4) for resource allocation (22).

C H A P T E R 10.1. 3 • Stereotactic Body Radiation Therapy for Localized Prostate Cancer

J J P OTE NTI A L BE N E FITS O F S BRT Radiobiology CFRT has several theoretical advantages of killing prostate cancer cells though the “3 Rs” of RT: (1) reoxygenation, that is, allowing more cells to become oxic, which makes RT more effective; (2) redistribution, that is, allowing for tumor cells to cycle into more radiosensitive phases of the cell cycle; and (3) repair, that is, allowing normal cells to repair sublethal damage. There is also a possibility of increasing tumor cell death and a minimizing radiation-related toxicity with higher doses per fraction. In general, as the total dose delivered increases, the number of surviving cells decreases. However, the advantages of increasing dose are countered by the toxicity to surrounding normal tissues. An α/β ratio is used to estimate the effects of radiation on tissues and compare various dose and fractionation schemes. The α/β ratio is generally believed to be >10 Gy for earlyresponding tissue (e.g., skin, mucosa, and most tumors); and it is believed to be 3 to 5 Gy for late-responding tissue (e.g., connective tissues, muscles), where genitourinary (GU) and gastrointestinal (GI) toxicity occurs. The α/β ratio is used in the calculation of the biologically equivalent dose (BED): BED = (nd[1 + d/(α/β)]), where n is the number of radiation fractions and d is the fraction size.

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Dose-escalated CFRT (a single 1.8–2.0 Gy fraction lasting 15 minutes per day, 5 days per week, up to ~80 Gy, for about 8 weeks) has been shown in multiple phase III randomized controlled trials to improve biochemical control over nondose-escalated fractionation schedules, which deliver the same Gy per fraction, but typically to a total dose of ~66 Gy (3–7). Using these two sample schedules, dose-escalated CFRT and nondose-escalated CFRT have BEDs (at an α/β ratio of 1.5 Gy) of 182 versus 154 Gy, respectively and (at an α/β ratio of 3.0 Gy) of 130 versus 110 Gy, respectively. In 2001, hypothesis-generating reports suggested that prostate cancer cells had a low α/β ratio of ~1.5 Gy, implying that the cells were more sensitive to large fraction doses (8). In addition, calculation models with an α/β ratio of 1.5 Gy showed that a prolonged course of RT (i.e., from CFRT) would be disadvantageous because (1) dose escalation is necessary to offset accelerated cancer cell repopulation (23); and (2) given the lower α/β ratio for prostate cancer than late-responding tissues, there would be potential for therapeutic gain and minimized toxicity to surrounding tissues with larger fraction sizes (9, 24). Thus, investigators have tried to maintain a high BED (at an α/β ratio of 1.5) to kill prostate cancer cells while minimizing the BED (at α/β ratios of 3–10) for toxicities. The BED curves for α/β ratios of 1.5 to 10 Gy for EBRT and sample SBRT schedules from articles included in this chapter are juxtaposed in Figure 10.1.3.1.

F I G U R E 10 .1. 3 .1 Biologically equivalent dose (BED) versus α/β ratios for stereotactic body radiation therapy (SBRT) compared with conven-

tionally fractionated radiation therapy (CFRT). A plot of BED curves for SBRT studies included in this chapter (gray lines); compared to CFRT to a total dose of 66 to 78 Gy in 2.0 Gy/fraction, for 33 to 39 fractions (dashed black lines).

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Radiophysics Since SBRT uses only one to five fractions to deliver the dose, there is little chance for adjustment once treatment has been initiated. Considerable time is spent by radiation oncologists and medical physicists ensure accuracy and precision in dose delivery on the treatment plan (25). Treatment planning is aided by advanced technologies that help to maximize dose to the tumor (minimizing dose to surrounding tissues), detect target movement, and compensate for movement. Two treatment delivering technologies used with SBRT help to achieve these goals: intensity-modulated radiation therapy (IMRT) and imageguided radiation therapy (IGRT). Currently, IMRT is the standard of care for prostate cancer because it maximizes the dose delivered to the tumor volume and minimizes the dose delivered to the surrounding organs. However, the sharp dose gradients that exist with IMRT plans could result in the volumetric error of missing the tumor because of the movement of the patient on the treatment table and the IGRT is a component of IMRT to ensure accuracy and precision of each fraction. IGRT detects and corrects random and systematic errors that occur during treatment delivery. Currently, multiple solutions exist for IGRT, including portal imaging using implanted fiducial markers (26), electromagnetic transponders (27), cone beam computed tomography (CT) (28), and CT-on-rails (29). IGRT has shown that the prostate moves daily, and these movements influence dosimetric coverage during RT. Prostate movements occur both interfractionally (i.e., between two RT sessions) (30, 31) and intrafractionally (i.e., during one RT session) (32, 33). The movements are also both translational (i.e., shifting of the isocenter) and rotational (i.e., around the isocenter). Although translations may be more easily detected and managed using image guidance, rotations are more difficult to detect and could cause significant underdosing (34). It is possible that a shortened treatment course with SBRT would lead to a reduction in intrafraction and interfraction motion compared to CFRT, thus decreasing toxicity, although this hypothesis has not yet been tested in clinical trials. The two major types of delivery systems of SBRT are gantry-based linear accelerators and the robotic arm-based systems. The conformality of robotic arm-based systems has been shown to be superior to IMRT, although the dose fall-off appears similar in both plans (35), and neither has been proven to be more efficacious than the other. The studies included in this chapter use both gantry-based and robotic arm-based systems. Patient Perspective Treatment options for low-risk, localized prostate cancer include CFRT, HFRT, RP, and BT. SBRT has unique

PART II • Treatment for Low-Risk, Localized Disease

advantages for the patient when compared with these options. The 8 weeks of therapy of CFRT is inconvenient to those who live far from treatment centers or have difficulty with travel. This long treatment course is the most frequently patient-cited disadvantage of CFRT (36). Moreover, CFRT has commonly associated early rectal toxicity, and sometimes late rectal, urinary, and sexual toxicities (37). Currently, HFRT is only available in the setting of clinical trials (20). Finally, although studies of both RP (38–44) and BT (41, 45–60) (both of which last for a few hours in 1 day) have shown improved biochemical outcomes, these modalities have limitations. RP commonly causes impotence and incontinence, and BT commonly causes irritative and obstructive urinary symptoms (37). Thus, the shorter treatment course (i.e., 2 weeks) and noninvasive nature of SBRT make it an attractive treatment option to patients with localized prostate cancer. Moreover, in certain regions of the world where RT centers may be difficult to access or are few in number, SBRT could become the standard of care. Resource Allocation SBRT has potential to improve resource allocation. Calculation models show that wage costs outweigh the cost of machines in RT; planning and delivery are labor intensive (61–64). Moreover, although treatment planning complexity is increasing with evolving technology, the planning is only done at the beginning of therapy. Cost, however, builds with the delivery of each fraction (65). Staffing RT facilities is estimated to account for 50% of their cost (66). Thus, changing from CFRT to an SBRT schedule may decrease the number of work hours and overall cost of treating each patient.

J J O UTCOM ES Results of efficacy from recent studies with SBRT are listed in Table 10.1.3.1 (67–81). The longest follow-up times currently available are at 5 years. Freedom from biochemical failure (FFBF) rates for low-, intermediate-, and high-risk patients have generally been ≥90% at up to 5 years. Outcomes from both gantry and robotic armbased systems have been similar: 2-year FFBF rates have been 90% to 100% versus 94% to 100%, respectively. There are a number of differences among SBRT, RP, and BT studies. Figure 10.1.3.2 shows the FFBF versus time of SBRT studies with the FFBF rates of low-risk patients in published studies of RP (38–44) and BT (41, 45–60) studies co-plotted. The mean median follow-up times of SBRT, RP, and BT studies are co-plotted on the inset in Figure 10.1.3.2. First, the follow-up times of SBRT studies

C H A P T E R 10.1. 3 • Stereotactic Body Radiation Therapy for Localized Prostate Cancer

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F I G U R E 10 .1. 3 . 2 Freedom from biochemical failure (FFBF) versus year plot of prostate cancer patients treated with stereotactic body radiation

therapy (SBRT), compared with those treated with brachytherapy (BT) and radical prostatectomy (RP). The y-axis shows the FFBF rate, and the x-axis shows time in years. Among the men treated with SBRT (circles), FFBF rates for low-, intermediate-, and high-risk patients have generally been ≥90% at up to 5 years (67–81). FFBF rates of low-risk patients from trials with BT(Xs) (41, 45–50) and RP (triangles) (38–44) are co-plotted for comparison. The mean median follow-up times (with their respective standard deviations) of SBRT, RP, and BT studies are co-plotted on the inset.

(mean 3.1 years) are significantly shorter than those of studies of RP (5.8 years) or BT (5.6 years). Second, there have been many more patients treated with RP and BT than SBRT (>20,000 vs.