Christopher R. King

Long-Term Outcomes From a Prospective Trial of Stereotactic Body Radiotherapy for Low-Risk Prostate Cancer

PURPOSE Hypofractionated radiotherapy has an intrinsically different normal tissue and tumor radiobiology. The results of a prospective trial of stereotactic body radiotherapy (SBRT) for prostate cancer with long-term patient-reported toxicity and tumor control rates are presented. METHODS AND MATERIALS From 2003 through 2009, 67 patients with clinically localized low-risk prostate cancer were enrolled. Treatment consisted of 36.25 Gy in 5 fractions using SBRT with the CyberKnife as the delivery technology. No patient received hormone therapy. Patient self-reported bladder and rectal toxicities were graded on the Radiation Therapy Oncology Group scale (RTOG). RESULTS Median follow-up was 2.7 years. There were no grade 4 toxicities. Radiation Therapy Oncology Group Grade 3, 2, and 1 bladder toxicities were seen in 3% (2 patients), 5% (3 patients), and 23% (13 patients) respectively. Dysuria exacerbated by urologic instrumentation accounted for both patients with Grade 3 toxicity. Urinary incontinence, complete obstruction, or persistent hematuria was not observed. Rectal Grade 3, 2, and 1 toxicities were seen in 0, 2% (1 patient), and 12.5% (7 patients), respectively. Persistent rectal bleeding was not observed. Low-grade toxicities were substantially less frequent with QOD vs. QD dose regimen (p = 0.001 for gastrointestinal and p = 0.007 for genitourinary). There were two prostate-specific antigen (PSA), biopsy-proven failures with negative metastatic workup. Median PSA at follow-up was 0.5 ± 0.72 ng/mL. The 4-year Kaplan-Meier PSA relapse-free survival was 94% (95% confidence interval, 85%-102%). CONCLUSION Significant late bladder and rectal toxicities from SBRT for prostate cancer are infrequent. PSA relapse-free survival compares favorably with other definitive treatments. The current evidence supports consideration of stereotactic body radiotherapy among the therapeutic options for localized prostate cancer.

Stereotactic body radiotherapy for localized prostate cancer: Pooled analysis from a multi-institutional consortium of prospective phase II trials

PURPOSE The effectiveness of stereotactic body radiotherapy (SBRT) for localized prostate cancer is tested. METHODS AND MATERIALS A total of 1100 patients with clinically localized prostate cancer were enrolled in separate prospective phase 2 clinical trials of SBRT from 8 institutions during 2003-11 and pooled for analysis. SBRT using the CyberKnife delivered a median dose of 36.25Gy in 4-5 fractions. Patients were low-risk (58%), intermediate-risk (30%) and high-risk (11%). A short-course of androgen deprivation therapy (ADT) was given to 14%. PSA relapse defined as a rise >2ng/ml above nadir was analyzed with the Kaplan Meier method. RESULTS With a median follow-up of 36months there were 49 patients with PSA failure (4.5%), 9 of whom were subsequently determined to be benign PSA bounces. The 5-year biochemical relapse free survival (bRFS) rate was 93% for all patients; 95%, 83% and 78% for GS ⩽6, 7 and ⩾8, respectively (p=0.001), and 95%, 84% and 81% for low-, intermediate- and high-risk patients, respectively (p<0.001). No differences were observed with ADT (p=0.71) or as a function of total dose (p=0.17). A PSA bounce of >0.2ng/ml was noted among 16% of patients. For 135 patients possessing a minimum of 5years follow-up, the 5-year bRFS rate for low- and intermediate-risk patients was 99% and 93%, respectively. CONCLUSION PSA relapse-free survival rates after SBRT compare favorably with other definitive treatments for low and intermediate risk patients. The current evidence supports consideration of SBRT among the therapeutic options for these patients.

Stereotactic body radiotherapy for low-risk prostate cancer: five-year outcomes

PurposeHypofractionated, stereotactic body radiotherapy (SBRT) is an emerging treatment approach for prostate cancer. We present the outcomes for low-risk prostate cancer patients with a median follow-up of 5 years after SBRT.Method and MaterialsBetween Dec. 2003 and Dec. 2005, a pooled cohort of 41 consecutive patients from Stanford, CA and Naples, FL received SBRT with CyberKnife for clinically localized, low-risk prostate cancer. Prescribed dose was 35-36.25 Gy in five fractions. No patient received hormone therapy. Kaplan-Meier biochemical progression-free survival (defined using the Phoenix method) and RTOG toxicity outcomes were assessed.ResultsAt a median follow-up of 5 years, the biochemical progression-free survival was 93% (95% CI = 84.7% to 100%). Acute side effects resolved within 1-3 months of treatment completion. There were no grade 4 toxicities. No late grade 3 rectal toxicity occurred, and only one late grade 3 genitourinary toxicity occurred following repeated urologic instrumentation.ConclusionFive-year results of SBRT for localized prostate cancer demonstrate the efficacy and safety of shorter courses of high dose per fraction radiation delivered with SBRT technique. Ongoing clinical trials are underway to further explore this treatment approach.

A simple analytic derivation suggests that prostate cancer α/β ratio is low

Since the publication of Brenner and Hall’s recent paper (1) suggesting that the a/b ratio for prostate cancer is 1.5 Gy, a debate has been propagated through the radiotherapy community (2–5). This surprisingly low value carries implications of more efficient (and perhaps less costly) regimens of external beam radiotherapy (i.e., hypofractionated schedules) and optimal forms of brachytherapy (i.e., high dose rate). Should it prove to be true, such a low ratio would negate the therapeutic advantage of conventional fractionation regimens and call out for clinical trials. There is certainly indirect evidence for a low a/b ratio. The very small proportion of proliferating cells (6, 7), the very long observed doubling times (8, 9), the slow response to irradiation, and the recent interim results of high-dose-rate brachytherapy of varying fractionation (10) are all are consistent with such a low value. The surprise is that this value is as low as, if not even lower than, normal tissue response to irradiation. Can one apply the linear-quadratic (LQ) equation to outcomes of a population of clinically localized prostate cancer after radiotherapy? The LQ equation, although purely phenomenological, has certainly proven to be of great use, both in the study of cultured tumor cells irradiated in vitro, in comparing regimens of different fractionation, and in the study of normal tissue response to radiation. Although issues of interand intratumor heterogeneity are not directly accounted for in the standard LQ formalism, these issues might not necessarily affect the a/b ratio when applied to changes in fraction size (4). Whereas the a term, a direct measure of radiosensitivity, does depend upon heterogeneity (3) and is intimately tied to the number of clonogens, the ratio a/b might not. We present a simple analytical derivation of a/b that is a logical conclusion from the observation that, for clinically localized prostate cancer, external beam and permanent brachytherapy appear to achieve equivalent outcomes. This derivation makes no assumptions and does not attempt to fit models to specific clinical data. For fractionated external-beam irradiation to a total dose De, with dose per fraction d, the LQ survival fraction of clonogens can be written as follows:

CyberKnife Radiotherapy for Localized Prostate Cancer: Rationale and Technical Feasibility

There is a clear dose response for localized prostate cancer radiotherapy and there probably is a radiobiological rationale for hypo-fractionation. Combining the two should maximize tumor control and increase the therapeutic ratio. This study examines the rationale and technical feasibility of CyberKnife radiotherapy (a robotic arm-driven linear accelerator) for localized prostate cancer. Its ability to deliver non-coplanar non-isocentric arcs can yield maximally conformal isodoses. It is the only integrated system capable of target position verification and real-time tracking during delivery of conformal stereotactic radiotherapy. Inverse planning with the CyberKnife is used to design a course of radiotherapy for localized prostate cancer. Fiducial markers within the gland are used to verify organ position and track organ motion via an orthogonal pair of electronic x-ray imaging devices and provide real-time feedback correction to the robotic arm during delivery. Conformal isodose curves and dose volume histograms (DVH) are used to compare with an optimized Intensity-Modulated Radiotherapy (IMRT) plan actually delivered to the study patient based upon CT scan-derived organ volumes. The CyberKnife can produce superior DVHs for sparing of rectum and bladder and excellent DVHs for target coverage compared with IMRT, and possesses dose heterogeneities to the same degree as IMRT plans. Because of the significantly longer delivery times required it would be best suited for hypo-fractionated regimens. Such dose regimens might allow for biologically equivalent dose escalation without increased normal tissue toxicity. Since the CyberKnife can verify organ position and motion and correct for this in real-time it is the ideal means of achieving such excellent DVHs without a compromise in doses to normal tissues. These capabilities are essential if one contemplates hypo-fractionated regimens with large dose-per-fraction sizes (>5Gy to 10Gy) and dose-escalation.

Intrafractional Motion of the Prostate During Hypofractionated Radiotherapy

PURPOSE To report the characteristics of prostate motion as tracked by the stereoscopic X-ray images of the implanted fiducials during hypofractionated radiotherapy with CyberKnife. METHODS AND MATERIALS Twenty-one patients with prostate cancer who were treated with CyberKnife between January 2005 and September 2007 were selected for this retrospective study. The CyberKnife uses a stereoscopic X-ray system to obtain the position of the prostate target through the monitoring of implanted gold fiducial markers. If there is a significant deviation, the treatment is paused while the patient is repositioned by moving the couch. The deviations calculated from X-ray images acquired within the time interval between two consecutive couch motions constitute a data set. RESULTS Included in the analysis were 427 data sets and 4,439 time stamps of X-ray images. The mean duration for each data set was 697 sec. At 30 sec, a motion >2 mm exists in about 5% of data sets. The percentage is increased to 8%, 11%, and 14% at 60 sec, 90 sec, and 120 sec, respectively. A similar trend exists for other values of prostate motion. CONCLUSIONS With proper monitoring and intervention during treatment, the prostate shifts observed among patients can be kept within the tracking range of the CyberKnife. On average, a sampling rate of approximately 40 sec between consecutive X-rays is acceptable to ensure submillimeter tracking. However, there is significant movement variation among patients, and a higher sampling rate may be necessary in some patients.

The Timing of Salvage Radiotherapy After Radical Prostatectomy: A Systematic Review

PURPOSE Salvage radiotherapy (SRT) after radical prostatectomy can potentially eradicate residual microscopic disease. Defining the optimal patient and treatment factors is essential and is particularly relevant within the context of adjuvant vs early vs delayed postoperative radiotherapy (RT). METHODS AND MATERIALS A systematic review of all published SRT studies was performed to identify the pathologic, clinical, and treatment factors associated with relapse-free survival (RFS) after SRT. A total of 41 studies encompassing 5597 patients satisfied the study entry criteria. Radiobiologic interpretation of biochemical tumor control was used to provide the framework for the observed relationships. RESULTS Prostate-specific antigen (PSA) level before SRT (P<.0001) and RT dose (P=.0052) had a significant and independent association with RFS. There was an average 2.6% loss of RFS for each incremental 0.1 ng/mL PSA at the time of SRT (95% CI, ∼2.2-3.1). With a PSA level of 0.2 ng/mL or less before SRT, the RFS approached 64%. The dose for salvage RT in the range of 60-70 Gy seemed to be on the steep part of the sigmoidal dose-response curve, with a dose of 70 Gy achieving 54% RFS compared with only 34% for 60 Gy. There was a 2% improvement in RFS for each additional Gy (95% CI, ∼0.9-3.2). The observed dose-response was less robust on sensitivity analysis. CONCLUSIONS This study provides Level 2a evidence for initiating SRT at the lowest possible PSA. Dose escalation is also suggested by the data. Progressively better tumor control rates with SRT after radical prostatectomy are achieved with a lower PSA at initiation and with a higher RT dose. Early salvage RT may be an equivalent strategy to adjuvant RT.

Health-Related Quality of Life After Stereotactic Body Radiation Therapy for Localized Prostate Cancer: Results From a Multi-institutional Consortium of Prospective Trials

PURPOSE To evaluate the early and late health-related quality of life (QOL) outcomes among prostate cancer patients following stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS Patient self-reported QOL was prospectively measured among 864 patients from phase 2 clinical trials of SBRT for localized prostate cancer. Data from the Expanded Prostate Cancer Index Composite (EPIC) instrument were obtained at baseline and at regular intervals up to 6 years. SBRT delivered a median dose of 36.25 Gy in 4 or 5 fractions. A short course of androgen deprivation therapy was given to 14% of patients. RESULTS Median follow-up was 3 years and 194 patients remained evaluable at 5 years. A transient decline in the urinary and bowel domains was observed within the first 3 months after SBRT which returned to baseline status or better within 6 months and remained so beyond 5 years. The same pattern was observed among patients with good versus poor baseline function and was independent of the degree of early toxicities. Sexual QOL decline was predominantly observed within the first 9 months, a pattern not altered by the use of androgen deprivation therapy or patient age. CONCLUSION Long-term outcome demonstrates that prostate SBRT is well tolerated and has little lasting impact on health-related QOL. A transient and modest decline in urinary and bowel QOL during the first few months after SBRT quickly recovers to baseline levels. With a large number of patients evaluable up to 5 years following SBRT, it is unlikely that unexpected late adverse effects will manifest themselves.

Radiotherapy After Prostatectomy: Is the Evidence for Dose Escalation out There?

PURPOSE To study the effective doses of radiotherapy (RT) after prostatectomy in search for evidence of a dose-response. METHODS AND MATERIALS Original and available data from published studies of adjuvant and salvage RT after prostatectomy were analyzed in the context of biochemical tumor control probability (TCP) dose-response curves. Comparisons were made with dose-escalation studies of radical RT for localized disease. Arguments based on a microscopic vs. macroscopic disease dose-response relationships were used to interpret the clinical data. RESULTS The tumor control rates after salvage RT were consistent with the TCP dose-response curve of radical RT, suggesting the presence of macroscopic-equivalent disease among salvage patients. For radical RT, the dose to achieve 50% biochemical tumor control was 65.9 Gy (95% confidence interval [CI], 64.8-66.8) and the Slope(50) was 2.6%/Gy (95% CI, 2.3-3.0). For salvage RT, the corresponding values were 66.8 Gy (95% CI, 65.1-68.4) and 3.8%/Gy (95% CI, 2.5-7.6). For a comparable TCP, the dose for adjuvant RT was approximately 6 Gy lower, consistent with one-tenth the burden of local disease. The present doses for adjuvant or salvage RT in the range of 60-70 Gy appear to be still on the steep part of the TCP dose-response curve. CONCLUSIONS The effective doses and dose-response relation observed with RT after prostatectomy are consistent with the presence of macroscopic-equivalent disease for salvage patients and about a tenth of the residual disease for adjuvant patients. Greater doses would potentially achieve significantly greater disease-free control rates. A randomized trial with 250 patients comparing 64 vs. 70 Gy for salvage RT or 60 vs. 66 Gy for adjuvant RT would be capable of addressing this issue.

Improved Outcomes With Higher Doses for Salvage Radiotherapy After Prostatectomy

PURPOSE To evaluate relapse-free survival with higher doses for patients receiving salvage radiotherapy (RT) after radical prostatectomy (RP). PATIENTS AND METHODS A total of 122 patients with pathologically negative lymph nodes received salvage RT after RP from 1984 to 2004. Median prostate bed dose was 60 Gy for 38 patients and 70 Gy for 84 patients. Four months of total androgen suppression and whole-pelvic RT were given concurrently to 68 and 72 patients, respectively. The median follow-up was >5 years. Kaplan-Meier and Cox proportional hazards multivariable analyses were performed for all clinical, pathologic, and treatment factors predicting for biochemical relapse-free survival (bRFS). RESULTS There were 60 biochemical failures after salvage RT, with a median time to failure of 1.2 years. A dose response was observed, with a 5-year bRFS rate of 25% vs. 58% for prostate bed doses of 60 Gy vs. 70 Gy (p < 0.0001). For patients receiving RT alone the 5-year bRFS rate was 17% vs. 55% (p = 0.016), and for those receiving prostate-bed-only RT it was 23% vs. 66% (p = 0.037) for doses of 60 Gy vs. 70 Gy, respectively. On multivariate analysis a prostate bed dose of 70 Gy (p = 0.012, hazard ratio [HR] 0.48 [95% Confidence Interval (CI), 0.27-0.87]), pre-RT prostate-specific antigen value < or =1 ng/mL (p < 0.0001, HR 0.28 [95% CI, 0.16-0.48]), and lack of seminal vesicle involvement (p = 0.009, HR 0.44 [95% CI, 0.26-0.77]) remained independently significant. CONCLUSIONS A clinically significant dose response from 60 Gy to 70 Gy was observed in the setting of salvage RT after prostatectomy. A dose of 70 Gy to the prostate bed is recommended to achieve optimal disease-free survival.