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

Stereotactic body radiotherapy for low-risk prostate cancer: five-year outcomes Purpose: Hypofractionated, 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 Materials: Between 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. Results: At 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. Conclusion: Five-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. Background Stereotactic body radiotherapy (SBRT) has recently Prostate cancer is thought to have unique radiobiology, emerged as an alternative technique to deliver hypofrac- characterized by a low a/b ratio relative to surrounding tionated radiotherapy to the prostate, comparable in normal tissues [1,2]. A growing body of evidence from many respects to HDR brachytherapy, but with a non- clinical studies using hypofractionated radiation provides invasive approach [8-14]. The concept is not entirely support that the a/b ratio for prostate cancer is lower novel. In the 1980 s, prostate cancer patients were trea- than that for the bladder and rectum, and that conse- ted in the United Kingdom with 6 fractions of 6 Gy quently a therapeutic gain could be achieved using each, delivered over three weeks. Good disease control fewer, high-dose fractions (see reviews by Dasu [3] and with no major early or late morbidity was obtained [15]. Macias and Biete [4]). High-dose-rate (HDR) bra- Innovations in image-guidance technology, the ability to chytherapy can deliver radiation to a tightly constrained automatically correct for the movement of the prostate treatment volume using large doses per fraction. Recent during treatment, and delivery of highly-conformal multi-institutional findings reported by Martinez et al. beam profiles have greatly enhanced the capability of delivering high dose fractions to a well-defined target, for early stage prostate cancer show a 5-year biochem- ical disease-free survival of about 90% for HDR with sharp dose fall-off towards the bladder and rectum brachytherapy, which is comparable to their own low- [16-18]. dose-rate (LDR) brachytherapy outcomes, with lower King et al. at Stanford University began treating low- late toxicity levels [5-7]. risk prostate cancer patients with the CyberKnife system (Accuray Inc.,Sunnyvale,CA)in late 2003,usingfive fractions of 7.25 Gy (total 36.25 Gy). At a median * Correspondence: dfreeman_md@yahoo.com follow-up of 33 months for the first 41 patients, the Naples Radiation Oncology, PA, USA urethral/rectal toxicity profile was comparable to that Full list of author information is available at the end of the article © 2011 Freeman and King; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Freeman and King Radiation Oncology 2011, 6:3 Page 2 of 5 http://www.ro-journal.com/content/6/1/3 from dose-escalated external beam radiotherapy (EBRT) Treatment Planning and Delivery [12]. Friedland and Freeman et al. in Naples, Florida, Three to four gold fiducial markers were placed in the began their SBRT program in early 2005, treating low- prostate under transrectal ultrasound guidance for and intermediate-risk patients with 5 fractions of 7.0 Gy image-guided positioning and motion tracking. Treat- (total 35 Gy). Outcomes from their first 112 patients ment planning CT scans were performed at a slice thickness of 1.25 mm, either on the same day (Stanford) showed a biochemical control rate of 97% at 24 months or one week after fiducial placement (Naples). MRI median follow-up and toxicity similar to or better than scans were obtained for all Naples patients, with pre- published outcomes of EBRT [9]. ferred sequences of T2* GRE or T1 post Gd, using a Given the intense level of interest in academic and community practices, the ramifications for the manage- slice thickness of 1-2 mm. Planning CTs were used ment of prostate cancer, and the potential positive eco- either alone (Stanford) or fused with MRI images nomic impact on prostate cancer treatments, we felt it (Naples), to differentiate the prostate and the proximal 1 would be both timely and of significant value to exam- cm of the seminal vesicles (the gross tumor volume, or ine outcomes from patients with the longest follow-up GTV) from the rectum, urogenital diaphragm, bladder, available to date with the aim of determining disease distal seminal vesicles, and other surrounding structures. control and toxicity for SBRT at a median of 5 years. In Theclinicaltargetvolumeconsisted of a3mm expan- this report, we present for the first time the results from sion anteriorly and laterally and a 1 mm posterior our combined experience. expansion. The planning target volume (PTV) consisted of an additional 2 mm expansion anteriorly and laterally Materials and methods and 2 mm posteriorly, to account for errors in target Patient Characteristics definition and delivery. The Stanford prostate SBRT program began in Decem- All patients were treated with the CyberKnife system, ber 2003. Eligible patients had newly diagnosed, composed of a 6 MV linear accelerator mounted on a biopsy-proven prostate cancer presenting with low-risk robotic arm, with two orthogonal kilovoltage X-ray ima- features. The criteria for low-risk classification gers that provide real-time stereoscopic image guidance and automatic correction for movements of the prostate included a pre-treatment PSA of 10 ng/mL or less, throughout treatment. Typically, 150-200 non-coplanar Gleason score of 3+3 or lower and clinical stage T1c beams were delivered in each treatment session. Patient or T2a/b. Patients with a Gleason score of 3+4 were positioning and target tracking were accomplished by included if present in 2 or fewer cores and involving registering the location of the fiducials in the real time less than 5 mm aggregate tumor length. Patients with images to their location in the planning CT. The robot prior treatment (hormone therapy or transurethral resection of prostate) were excluded. The Naples pro- automatically corrected the accelerator’s aim to account spective program began in February 2005. Eligibility for both translational and rotational movement of the criteria were similar to that of the Stanford program, patient or prostate during the treatment. except that it included patients with Gleason scores 3 Treatment for the Stanford patients consisted of 5 +4 in addition to those with Gleason scores of 3+3. fractions of 7.25 Gy for a total dose of 36.25 Gy. The For the current study, we included only the Naples prescription dose covered at least 95% of the planning patients with Gleason scores of 3+3 or lower, to target volume, normalized to the 88-92% isodose line. increase the homogeneity of this combined study The rectal dose-volume goals were <50% of the rectum population. Staging work-up included a bone scan and receiving 50% of the prescribed dose, <20% receiving CT scan of the abdomen and pelvis. Both centers had 80% of the dose, <10% receiving 90% of the dose, and IRB-approval for enrolling patients in their clinical <5% receiving 100% of the dose. The Naples patients trial. received 5 fractions of 7 Gy each, for a total dose of 35 The current patient cohort consists of consecutively Gy. The planning objective was also to deliver the pre- treated patients with the longest follow-up participating scribed dose to at least 95% of the PTV. For the rectum, in the Stanford [12] and Naples studies [9]. Two the V36 Gy constraint was <1 cm ;for thebladder, the patients were lost to follow-up within 12 months of V37 Gy was <10 cm . The Stanford rectal dose-volume treatment and were not included. Two others died of guidelines were followed whenever possible. Treatments non-prostate cancer related disease at 12 and 51 months were given over 5 consecutive days for all but 3 patients in the combined cohort. after treatment. This study is therefore composed of 41 patients with a median follow-up of 5 years (4.2-6.2 Follow-up and Toxicity Scoring years). The median patient age was 66 years (range 48 Patients were followed every 3 months during the first to 83 years). The median initial PSA was 5.6 ng/mL (range 0.7 to 10 ng/mL). year and every 6-12 months thereafter. PSA levels were Freeman and King Radiation Oncology 2011, 6:3 Page 3 of 5 http://www.ro-journal.com/content/6/1/3 obtained at each follow-up. Toxicity and quality of life Toxicity measures for Stanford patients were assessed using the As previously reported, patients tolerated treatments EPIC scale. Naples patients were assessed with the very well, resuming normal activities within one week of American Urological Association (AUA) and Sexual completion. Acute symptoms of dysuria, urinary Health Inventory for Men (SHIM) surveys. Toxicities urgency, frequency, nocturia and/or tenesmus typically resolved within one month of treatment completion. were subsequently scored based on Radiation Therapy Late toxicities are summarized in Table 1. No patient Oncology Group (RTOG) urinary and rectal toxicity cri- has experienced grade 3 or greater late rectal toxicity. teria [19], and toxicities requiring intervention were Only one patient developed late grade 3 urinary toxicity noted. (The authors acknowledge that the RTOG scor- ing system may be insensitive to subtle changes in urin- following repeated urologic instrumentation, including ary or bowel function.) Biochemical failure was assessed cystoscopy and urethral dilatation. No urinary inconti- using the nadir+2 (Phoenix) definition [20]. nence has been observed. Twenty-five percent of patients reported mild (grade 1) and 7% moderate Results (grade 2) urinary symptoms following treatment. King et PSA Response al. [12] previously reported less frequent grade 1-2 urin- The 5-year biochemical progression-free survival rate ary toxicity when SBRT treatments were delivered on was 92.7% (95% CI = 84.7% to 100%, Figure 1). PSA fell non-consecutive days (QOD) vs. daily (QD). As the from a pre-treatment mean (± SD) of 5.4 ± 2.4 ng/ml to majority of patients in this study received QD treatment, a mean post-treatment value of 0.34 ± 0.35 ng/ml at last a similar comparison was not possible. follow-up for non-recurring patients. Median PSA nadir was 0.3 ng/ml. Comparing non-recurring Stanford Discussion patients (treated with 36.25 Gy) to Naples patients (trea- This report demonstrates that SBRT can achieve high ted with 35 Gy), the mean PSA at last follow-up was rates of durable disease control for patients with low- significantly lower for the Stanford group (0.18 ± 0.14 risk prostate cancer while resulting in low levels of blad- ng/ml vs. 0.51 ± 0.46 ng/ml, p = 0.002). The mean fol- der and rectal toxicity. The current results extend prior low-up for the Stanford patients was about 4.5 months independently conducted studies by the authors [9,12], longer than for the Naples patients (5.17 vs. 4.78 years). demonstrating the potential of SBRT monotherapy to provide durable disease control with few serious compli- Three patients developed biochemical progression at 33, cations in low-risk prostate cancer patients. Our 5-year 37 and 42 months, respectively. Two patients received progression-free survival rate of 93% compares favorably the 35 Gy dose; the third received 36.25 Gy. In each case, biopsy confirmed pathologic evidence of malig- with that obtained with surgery, LDR or HDR bra- nancy within the prostate gland and a negative meta- chytherapy [21-26]. static work-up. The remaining patients continued to In a recent update of the Stanford experience, which have stable or declining PSA levels at last follow-up. included 67 low-risk patients [27], King et al. succinctly reviewed the rationale for hypofractionation in the man- agement of prostate cancer. At a median follow-up of 2.7 years, the PSA relapse-free survival was 94%, and toxicity was equal to or lower than observed in dose- escalation studies. Disease control rates above 90% are entirely consistent with predictions based on an a/b ratio for prostate cancer of 1.5 Gy. Using the linear- quadratic radiobiologic model, 36.25 Gy yields an equivalent dose at 2 Gy per fraction, or EQD2, of 91 Gy for this a/b. In addition, both disease control and toxicity outcomes with SBRT compare favorably to other treatments for Table 1 Late urinary and rectal toxicity on the RTOG scale for prostate cancer patients after SBRT RTOG Grade I II III IV Figure 1 Kaplan-Meier biochemical disease-free survival curve Urinary 25% (10/41) 7% (3/41) 2.5% (1/41) 0% after SBRT for prostate cancer. Median follow-up is 5-years. Three of the 41 patients recurred, at 33, 37 and 42 months post-treatment. Rectal 13% 2.5% 0% 0% Tick marks indicate censored patients. (6/41) (1/41) Freeman and King Radiation Oncology 2011, 6:3 Page 4 of 5 http://www.ro-journal.com/content/6/1/3 low-risk prostate cancer. In a study comparing outcomes available therapies, with equal to or better toxicity pro- for radical prostatectomy and IMRT to a dose of at least files. In addition, the treatment can be completed in a 72 Gy [28], no significant difference in 5-year biochem- time period that is notably shorter (1-2 weeks) than ical disease-free survival (bDFS) rates was detected for conventional radiotherapy (8-9 weeks) and neither low-risk patients (prostatectomy resulted in a bDFS of hospitalization nor surgical recovery is involved. These 92.8% vs. 85.3% for IMRT, p = 0.20). Similar 5-year bDFS characteristics of SBRT may benefit patients by reducing rates, ranging from 76% to 92% for radical prostatectomy, travel costs and lost work time, allowing a more 69% to 89% for external beam radiotherapy at doses of 66 immediate return to normal, daily routines, and poten- to 72 Gy, and 83% to 88% for seed brachytherapy, have tially reducing health care costs. We look forward to been reported in retrospective comparisons of these future multicenter studies that will examine outcomes various treatments [21-26]. A recent report of a multi- with this treatment approach. institutional retrospective study comparing HDR bra- chytherapy to seed brachytherapy showed bDFS to be about 90% for both modalities. Somewhat higher 5-year Author details 1 2 Naples Radiation Oncology, PA, USA. Department of Radiation Oncology, bDFS rates, in the 92-95% range, have been obtained in UCLA School of Medicine, CA, USA. other studies of surgery, high-dose and hypofractionated EBRT, and seed brachytherapy for low-risk patients Authors’ contributions Both authors contributed equally to the conduct of the study and the [29-32]. Thus, the 5-year bDFS of 92.7% obtained in the contribution of patient data to the analysis. DF conducted analyses and current study is clearly within the range of disease con- wrote the initial draft of the paper. Both authors read and approved the trol expected using modern surgical and high-dose radia- final manuscript. tion techniques. Competing interests In the coming years, the long-term outcomes of several DF has received reimbursement as a consultant/employee for Accuray, Inc. other studies of SBRT for organ-confined prostate cancer CK has no financial conflicts of interest. will be reported. Katz et al. reported 3-year results on Received: 13 October 2010 Accepted: 10 January 2011 304 patients with low- and intermediate-risk disease, Published: 10 January 2011 with favorable outcomes [11]. An update with 42 months median follow up was presented at ASTRO 2010 [33], References 1. Brenner DJ, Hall EJ: Fractionation and protraction for radiotherapy of and 5-year data from this study should be available in prostate carcinoma. Int J Radiat Oncol Biol Phys 1999, 43:1095-1101. 2011. An additional 114 low-intermediate risk prostate 2. Fowler JF, Ritter MA, Chappell RJ, Brenner DJ: What hypofractionated patients were treated with SBRT in Naples in 2006, so protocols should be tested for prostate cancer? Int J Radiat Oncol Biol Phys 2003, 56:1093-1104. that data will reach 5-year maturity next year. Acute toxi- 3. Dasu A: Is the alpha/beta value for prostate tumours low enough to be city from a prospective study underway at the University safely used in clinical trials? Clin Oncol (R Coll Radiol) 2007, 19:289-301. Hospitals Case Medical Center were presented at the 4. Macias V, Biete A: Hypofractionated radiotherapy for localised prostate cancer. Review of clinical trials. Clin Transl Oncol 2009, 11:437-445. 2009 ASCO meeting [34]. Georgetown has also treated 5. Grills IS, Martinez AA, Hollander M, Huang R, Goldman K, Chen PY, prostate cancer using SBRT; early data were presented at Gustafson GS: High dose rate brachytherapy as prostate cancer the 2010 ASCO meeting [35]. Two prospective studies monotherapy reduces toxicity compared to low dose rate palladium seeds. J Urol 2004, 171:1098-1104. funded by Accuray, examining the effects of delivering 6. Martinez AA, Demanes J, Vargas C, Schour L, Ghilezan M, Gustafson GS: either a homogeneous, EBRT-like dose distribution or an High-Dose-Rate Prostate Brachytherapy: An Excellent Accelerated- HDR-like, heterogeneous distribution [10] should com- Hypofractionated Treatment for Favorable Prostate Cancer. Am J Clin Oncol 2010, 33(5):481-8. plete enrollment in the next 6 months, adding another 7. Yoshioka Y, Konishi K, Oh RJ, Sumida I, Yamazaki H, Nakamura S, 600 patients to the collective data pool. A phase III study Nishimura K, Nonomura N, Okuyama A, Inoue T: High-dose-rate comparing 12-fraction versus 5-fraction SBRT for loca- brachytherapy without external beam irradiation for locally advanced prostate cancer. Radiother Oncol 2006, 80:62-68. lized prostate cancer is currently under review by the 8. Aluwini S, van Rooij P, Hoogeman M, Bangma C, Kirkels WJ, Incrocci L, RTOG, and a proposed, phase III study from the Univer- Kolkman-Deurloo IK: CyberKnife stereotactic radiotherapy as sity of Miami will compare extended fractionation (26 monotherapy for low- to intermediate-stage prostate cancer: early experience, feasibility, and tolerance. J Endourol 2010, 24:865-869. fractions) versus accelerated hypofractionation (5 frac- 9. Friedland JL, Freeman DE, Masterson-McGary ME, Spellberg DM: tions) for low-intermediate risk disease. As data from Stereotactic body radiotherapy: an emerging treatment approach for these various studies mature, we will develop a clearer localized prostate cancer. Technol Cancer Res Treat 2009, 8:387-392. 10. Fuller DB, Naitoh J, Lee C, Hardy S, Jin H: Virtual HDR(SM) CyberKnife picture of long-term outcomes following SBRT. Treatment for Localized Prostatic Carcinoma: Dosimetry Comparison With HDR Brachytherapy and Preliminary Clinical Observations. Int J Conclusion Radiat Oncol Biol Phys 2008, 70:1588-1597. 11. Katz AJ, Santoro M, Ashley R, Diblasio F, Witten M: Stereotactic body The current analysis is the first report of 5-year out- radiotherapy for organ-confined prostate cancer. BMC Urol 2010, 10:1. comes of SBRT for low-risk prostate cancer, and bio- 12. King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, Presti JC Jr: Stereotactic chemical disease control is comparable to other body radiotherapy for localized prostate cancer: interim results of a Freeman and King Radiation Oncology 2011, 6:3 Page 5 of 5 http://www.ro-journal.com/content/6/1/3 prospective phase II clinical trial. Int J Radiat Oncol Biol Phys 2009, 30. Grimm PD, Blasko JC, Sylvester JE, Meier RM, Cavanagh W: 10-year 73:1043-1048. biochemical (prostate-specific antigen) control of prostate cancer with 13. Madsen BL, Hsi RA, Pham HT, Fowler JF, Esagui L, Corman J: Stereotactic (125)I brachytherapy. Int J Radiat Oncol Biol Phys 2001, 51:31-40. hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy 31. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC: Long-term biochemical in five fractions for localized disease: first clinical trial results. Int J Radiat disease-free and cancer-specific survival following anatomic radical Oncol Biol Phys 2007, 67:1099-1105. retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol 14. Townsend NC, Huth BJ, Ding W, Garber B, Mooreville M, Arrigo S, Clin North Am 2001, 28:555-565. Lamond J, Brady LW: Acute toxicity after CyberKnife-delivered 32. Kupelian PA, Thakkar VV, Khuntia D, Reddy CA, Klein EA, Mahadevan A: hypofractionated radiotherapy for treatment of prostate cancer. Am J Hypofractionated intensity-modulated radiotherapy (70 gy at 2.5 Gy per Clin Oncol 2010. fraction) for localized prostate cancer: long-term outcomes. Int J Radiat 15. Lloyd-Davies RW, Collins CD, Swan AV: Carcinoma of prostate treated by Oncol Biol Phys 2005, 63:1463-1468. radical external beam radiotherapy using hypofractionation. Twenty-two 33. Katz AJ, Santoro M: Quality of life and efficacy for stereotactic body years’ experience (1962-1984). Urology 1990, 36:107-111. radiotherapy for treatment of organ confined prostate cancer. Annual 16. Hossain S, Xia P, Chuang C, Verhey L, Gottschalk AR, Mu G, Ma L: Simulated Meeting of the Association for Radiation Oncology. San Diego, CA 2010. real time image guided intrafraction tracking-delivery for 34. Ponsky LE, Lillibridge C, Brindle J, Zhang Y, Wessels B, Einstein DB: hypofractionated prostate IMRT. Med Phys 2008, 35:4041-4048. Stereotactic robotic radiosurgery for localized prostate cancer: Initial 17. Hossain S, Xia P, Huang K, Descovich M, Chuang C, Gottschalk AR, Roach M, evaluation of acute toxicities. 2009 ASCO Annual Meeting. Orlando, Florida Ma L: Dose gradient gear target-normal structure interface for 2009. nonisocentric CyberKnife and isocentric intensity-modulated body 35. Oermann E, Hanscom HS, Lei S, Suy S, Chen V, Collins BT, Dritschilo A, radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2010. Lynch JH, Dawson NA, Collins SP: Hypofractionated robotic radiosurgery 18. Xie Y, Djajaputra D, King CR, Hossain S, Ma L, Xing L: Intrafractional motion for the treatment of clinically localized prostate cancer: Early of the prostate during hypofractionated radiotherapy. Int J Radiat Oncol biochemical results and acute toxicity. 2010 ASCO Annual Meeting Biol Phys 2008, 72:236-246. Chicago, IL 2010. 19. Cox JD, Stetz J, Pajak TF: Toxicity criteria of the Radiation Therapy doi:10.1186/1748-717X-6-3 Oncology Group (RTOG) and the European Organization for Research Cite this article as: Freeman and King: Stereotactic body radiotherapy and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995, for low-risk prostate cancer: five-year outcomes. Radiation Oncology 2011 31:1341-1346. 6:3. 20. Abramowitz MC, Li T, Buyyounouski MK, Ross E, Uzzo RG, Pollack A, Horwitz EM: The Phoenix definition of biochemical failure predicts for overall survival in patients with prostate cancer. Cancer 2008, 112:55-60. 21. D’Amico AV, Whittington R, Kaplan I, Beard C, Schultz D, Malkowicz SB, Tomaszewski JE, Wein A, Coleman CN: Equivalent 5-year bNED in select prostate cancer patients managed with surgery or radiation therapy despite exclusion of the seminal vesicles from the CTV. Int J Radiat Oncol Biol Phys 1997, 39:335-340. 22. D’Amico AV, Whittington R, Malkowicz SB, Cote K, Loffredo M, Schultz D, Chen MH, Tomaszewski JE, Renshaw AA, Wein A, Richie JP: Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era. Cancer 2002, 95:281-286. 23. D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, Wein A: Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. Jama 1998, 280:969-974. 24. Keyser D, Kupelian PA, Zippe CD, Levin HS, Klein EA: Stage T1-2 prostate cancer with pretreatment prostate-specific antigen level < or = 10 ng/ ml: radiation therapy or surgery? Int J Radiat Oncol Biol Phys 1997, 38:723-729. 25. Kupelian PA, Potters L, Khuntia D, Ciezki JP, Reddy CA, Reuther AM, Carlson TP, Klein EA: Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy > or = 72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1-T2 prostate cancer. Int J Radiat Oncol Biol Phys 2004, 58:25-33. 26. Martinez AA, Gonzalez JA, Chung AK, Kestin LL, Balasubramaniam M, Diokno AC, Ziaja EL, Brabbins DS, Vicini FA: A comparison of external beam radiation therapy versus radical prostatectomy for patients with low risk prostate carcinoma diagnosed, staged, and treated at a single institution. Cancer 2000, 88:425-432. Submit your next manuscript to BioMed Central 27. King CR, Brooks JD, Gill H, Presti JCJ: Long-term outcomes from a and take full advantage of: prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. Int J Radiat Oncol Biol Phys 2010. • Convenient online submission 28. Aizer AA, Yu JB, Colberg JW, McKeon AM, Decker RH, Peschel RE: Radical prostatectomy vs. intensity-modulated radiation therapy in the • Thorough peer review management of localized prostate adenocarcinoma. Radiother Oncol • No space constraints or color figure charges 2009, 93:185-191. • Immediate publication on acceptance 29. Cahlon O, Zelefsky MJ, Shippy A, Chan H, Fuks Z, Yamada Y, Hunt M, Greenstein S, Amols H: Ultra-high dose (86.4 Gy) IMRT for localized • Inclusion in PubMed, CAS, Scopus and Google Scholar prostate cancer: toxicity and biochemical outcomes. Int J Radiat Oncol • Research which is freely available for redistribution Biol Phys 2008, 71:330-337. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

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

Radiation Oncology , Volume 6 (1) – Jan 10, 2011

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Copyright © 2011 by Freeman and King; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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Abstract

Purpose: Hypofractionated, 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 Materials: Between 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. Results: At 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. Conclusion: Five-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. Background Stereotactic body radiotherapy (SBRT) has recently Prostate cancer is thought to have unique radiobiology, emerged as an alternative technique to deliver hypofrac- characterized by a low a/b ratio relative to surrounding tionated radiotherapy to the prostate, comparable in normal tissues [1,2]. A growing body of evidence from many respects to HDR brachytherapy, but with a non- clinical studies using hypofractionated radiation provides invasive approach [8-14]. The concept is not entirely support that the a/b ratio for prostate cancer is lower novel. In the 1980 s, prostate cancer patients were trea- than that for the bladder and rectum, and that conse- ted in the United Kingdom with 6 fractions of 6 Gy quently a therapeutic gain could be achieved using each, delivered over three weeks. Good disease control fewer, high-dose fractions (see reviews by Dasu [3] and with no major early or late morbidity was obtained [15]. Macias and Biete [4]). High-dose-rate (HDR) bra- Innovations in image-guidance technology, the ability to chytherapy can deliver radiation to a tightly constrained automatically correct for the movement of the prostate treatment volume using large doses per fraction. Recent during treatment, and delivery of highly-conformal multi-institutional findings reported by Martinez et al. beam profiles have greatly enhanced the capability of delivering high dose fractions to a well-defined target, for early stage prostate cancer show a 5-year biochem- ical disease-free survival of about 90% for HDR with sharp dose fall-off towards the bladder and rectum brachytherapy, which is comparable to their own low- [16-18]. dose-rate (LDR) brachytherapy outcomes, with lower King et al. at Stanford University began treating low- late toxicity levels [5-7]. risk prostate cancer patients with the CyberKnife system (Accuray Inc.,Sunnyvale,CA)in late 2003,usingfive fractions of 7.25 Gy (total 36.25 Gy). At a median * Correspondence: dfreeman_md@yahoo.com follow-up of 33 months for the first 41 patients, the Naples Radiation Oncology, PA, USA urethral/rectal toxicity profile was comparable to that Full list of author information is available at the end of the article © 2011 Freeman and King; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Freeman and King Radiation Oncology 2011, 6:3 Page 2 of 5 http://www.ro-journal.com/content/6/1/3 from dose-escalated external beam radiotherapy (EBRT) Treatment Planning and Delivery [12]. Friedland and Freeman et al. in Naples, Florida, Three to four gold fiducial markers were placed in the began their SBRT program in early 2005, treating low- prostate under transrectal ultrasound guidance for and intermediate-risk patients with 5 fractions of 7.0 Gy image-guided positioning and motion tracking. Treat- (total 35 Gy). Outcomes from their first 112 patients ment planning CT scans were performed at a slice thickness of 1.25 mm, either on the same day (Stanford) showed a biochemical control rate of 97% at 24 months or one week after fiducial placement (Naples). MRI median follow-up and toxicity similar to or better than scans were obtained for all Naples patients, with pre- published outcomes of EBRT [9]. ferred sequences of T2* GRE or T1 post Gd, using a Given the intense level of interest in academic and community practices, the ramifications for the manage- slice thickness of 1-2 mm. Planning CTs were used ment of prostate cancer, and the potential positive eco- either alone (Stanford) or fused with MRI images nomic impact on prostate cancer treatments, we felt it (Naples), to differentiate the prostate and the proximal 1 would be both timely and of significant value to exam- cm of the seminal vesicles (the gross tumor volume, or ine outcomes from patients with the longest follow-up GTV) from the rectum, urogenital diaphragm, bladder, available to date with the aim of determining disease distal seminal vesicles, and other surrounding structures. control and toxicity for SBRT at a median of 5 years. In Theclinicaltargetvolumeconsisted of a3mm expan- this report, we present for the first time the results from sion anteriorly and laterally and a 1 mm posterior our combined experience. expansion. The planning target volume (PTV) consisted of an additional 2 mm expansion anteriorly and laterally Materials and methods and 2 mm posteriorly, to account for errors in target Patient Characteristics definition and delivery. The Stanford prostate SBRT program began in Decem- All patients were treated with the CyberKnife system, ber 2003. Eligible patients had newly diagnosed, composed of a 6 MV linear accelerator mounted on a biopsy-proven prostate cancer presenting with low-risk robotic arm, with two orthogonal kilovoltage X-ray ima- features. The criteria for low-risk classification gers that provide real-time stereoscopic image guidance and automatic correction for movements of the prostate included a pre-treatment PSA of 10 ng/mL or less, throughout treatment. Typically, 150-200 non-coplanar Gleason score of 3+3 or lower and clinical stage T1c beams were delivered in each treatment session. Patient or T2a/b. Patients with a Gleason score of 3+4 were positioning and target tracking were accomplished by included if present in 2 or fewer cores and involving registering the location of the fiducials in the real time less than 5 mm aggregate tumor length. Patients with images to their location in the planning CT. The robot prior treatment (hormone therapy or transurethral resection of prostate) were excluded. The Naples pro- automatically corrected the accelerator’s aim to account spective program began in February 2005. Eligibility for both translational and rotational movement of the criteria were similar to that of the Stanford program, patient or prostate during the treatment. except that it included patients with Gleason scores 3 Treatment for the Stanford patients consisted of 5 +4 in addition to those with Gleason scores of 3+3. fractions of 7.25 Gy for a total dose of 36.25 Gy. The For the current study, we included only the Naples prescription dose covered at least 95% of the planning patients with Gleason scores of 3+3 or lower, to target volume, normalized to the 88-92% isodose line. increase the homogeneity of this combined study The rectal dose-volume goals were <50% of the rectum population. Staging work-up included a bone scan and receiving 50% of the prescribed dose, <20% receiving CT scan of the abdomen and pelvis. Both centers had 80% of the dose, <10% receiving 90% of the dose, and IRB-approval for enrolling patients in their clinical <5% receiving 100% of the dose. The Naples patients trial. received 5 fractions of 7 Gy each, for a total dose of 35 The current patient cohort consists of consecutively Gy. The planning objective was also to deliver the pre- treated patients with the longest follow-up participating scribed dose to at least 95% of the PTV. For the rectum, in the Stanford [12] and Naples studies [9]. Two the V36 Gy constraint was <1 cm ;for thebladder, the patients were lost to follow-up within 12 months of V37 Gy was <10 cm . The Stanford rectal dose-volume treatment and were not included. Two others died of guidelines were followed whenever possible. Treatments non-prostate cancer related disease at 12 and 51 months were given over 5 consecutive days for all but 3 patients in the combined cohort. after treatment. This study is therefore composed of 41 patients with a median follow-up of 5 years (4.2-6.2 Follow-up and Toxicity Scoring years). The median patient age was 66 years (range 48 Patients were followed every 3 months during the first to 83 years). The median initial PSA was 5.6 ng/mL (range 0.7 to 10 ng/mL). year and every 6-12 months thereafter. PSA levels were Freeman and King Radiation Oncology 2011, 6:3 Page 3 of 5 http://www.ro-journal.com/content/6/1/3 obtained at each follow-up. Toxicity and quality of life Toxicity measures for Stanford patients were assessed using the As previously reported, patients tolerated treatments EPIC scale. Naples patients were assessed with the very well, resuming normal activities within one week of American Urological Association (AUA) and Sexual completion. Acute symptoms of dysuria, urinary Health Inventory for Men (SHIM) surveys. Toxicities urgency, frequency, nocturia and/or tenesmus typically resolved within one month of treatment completion. were subsequently scored based on Radiation Therapy Late toxicities are summarized in Table 1. No patient Oncology Group (RTOG) urinary and rectal toxicity cri- has experienced grade 3 or greater late rectal toxicity. teria [19], and toxicities requiring intervention were Only one patient developed late grade 3 urinary toxicity noted. (The authors acknowledge that the RTOG scor- ing system may be insensitive to subtle changes in urin- following repeated urologic instrumentation, including ary or bowel function.) Biochemical failure was assessed cystoscopy and urethral dilatation. No urinary inconti- using the nadir+2 (Phoenix) definition [20]. nence has been observed. Twenty-five percent of patients reported mild (grade 1) and 7% moderate Results (grade 2) urinary symptoms following treatment. King et PSA Response al. [12] previously reported less frequent grade 1-2 urin- The 5-year biochemical progression-free survival rate ary toxicity when SBRT treatments were delivered on was 92.7% (95% CI = 84.7% to 100%, Figure 1). PSA fell non-consecutive days (QOD) vs. daily (QD). As the from a pre-treatment mean (± SD) of 5.4 ± 2.4 ng/ml to majority of patients in this study received QD treatment, a mean post-treatment value of 0.34 ± 0.35 ng/ml at last a similar comparison was not possible. follow-up for non-recurring patients. Median PSA nadir was 0.3 ng/ml. Comparing non-recurring Stanford Discussion patients (treated with 36.25 Gy) to Naples patients (trea- This report demonstrates that SBRT can achieve high ted with 35 Gy), the mean PSA at last follow-up was rates of durable disease control for patients with low- significantly lower for the Stanford group (0.18 ± 0.14 risk prostate cancer while resulting in low levels of blad- ng/ml vs. 0.51 ± 0.46 ng/ml, p = 0.002). The mean fol- der and rectal toxicity. The current results extend prior low-up for the Stanford patients was about 4.5 months independently conducted studies by the authors [9,12], longer than for the Naples patients (5.17 vs. 4.78 years). demonstrating the potential of SBRT monotherapy to provide durable disease control with few serious compli- Three patients developed biochemical progression at 33, cations in low-risk prostate cancer patients. Our 5-year 37 and 42 months, respectively. Two patients received progression-free survival rate of 93% compares favorably the 35 Gy dose; the third received 36.25 Gy. In each case, biopsy confirmed pathologic evidence of malig- with that obtained with surgery, LDR or HDR bra- nancy within the prostate gland and a negative meta- chytherapy [21-26]. static work-up. The remaining patients continued to In a recent update of the Stanford experience, which have stable or declining PSA levels at last follow-up. included 67 low-risk patients [27], King et al. succinctly reviewed the rationale for hypofractionation in the man- agement of prostate cancer. At a median follow-up of 2.7 years, the PSA relapse-free survival was 94%, and toxicity was equal to or lower than observed in dose- escalation studies. Disease control rates above 90% are entirely consistent with predictions based on an a/b ratio for prostate cancer of 1.5 Gy. Using the linear- quadratic radiobiologic model, 36.25 Gy yields an equivalent dose at 2 Gy per fraction, or EQD2, of 91 Gy for this a/b. In addition, both disease control and toxicity outcomes with SBRT compare favorably to other treatments for Table 1 Late urinary and rectal toxicity on the RTOG scale for prostate cancer patients after SBRT RTOG Grade I II III IV Figure 1 Kaplan-Meier biochemical disease-free survival curve Urinary 25% (10/41) 7% (3/41) 2.5% (1/41) 0% after SBRT for prostate cancer. Median follow-up is 5-years. Three of the 41 patients recurred, at 33, 37 and 42 months post-treatment. Rectal 13% 2.5% 0% 0% Tick marks indicate censored patients. (6/41) (1/41) Freeman and King Radiation Oncology 2011, 6:3 Page 4 of 5 http://www.ro-journal.com/content/6/1/3 low-risk prostate cancer. In a study comparing outcomes available therapies, with equal to or better toxicity pro- for radical prostatectomy and IMRT to a dose of at least files. In addition, the treatment can be completed in a 72 Gy [28], no significant difference in 5-year biochem- time period that is notably shorter (1-2 weeks) than ical disease-free survival (bDFS) rates was detected for conventional radiotherapy (8-9 weeks) and neither low-risk patients (prostatectomy resulted in a bDFS of hospitalization nor surgical recovery is involved. These 92.8% vs. 85.3% for IMRT, p = 0.20). Similar 5-year bDFS characteristics of SBRT may benefit patients by reducing rates, ranging from 76% to 92% for radical prostatectomy, travel costs and lost work time, allowing a more 69% to 89% for external beam radiotherapy at doses of 66 immediate return to normal, daily routines, and poten- to 72 Gy, and 83% to 88% for seed brachytherapy, have tially reducing health care costs. We look forward to been reported in retrospective comparisons of these future multicenter studies that will examine outcomes various treatments [21-26]. A recent report of a multi- with this treatment approach. institutional retrospective study comparing HDR bra- chytherapy to seed brachytherapy showed bDFS to be about 90% for both modalities. Somewhat higher 5-year Author details 1 2 Naples Radiation Oncology, PA, USA. Department of Radiation Oncology, bDFS rates, in the 92-95% range, have been obtained in UCLA School of Medicine, CA, USA. other studies of surgery, high-dose and hypofractionated EBRT, and seed brachytherapy for low-risk patients Authors’ contributions Both authors contributed equally to the conduct of the study and the [29-32]. Thus, the 5-year bDFS of 92.7% obtained in the contribution of patient data to the analysis. DF conducted analyses and current study is clearly within the range of disease con- wrote the initial draft of the paper. Both authors read and approved the trol expected using modern surgical and high-dose radia- final manuscript. tion techniques. Competing interests In the coming years, the long-term outcomes of several DF has received reimbursement as a consultant/employee for Accuray, Inc. other studies of SBRT for organ-confined prostate cancer CK has no financial conflicts of interest. will be reported. Katz et al. reported 3-year results on Received: 13 October 2010 Accepted: 10 January 2011 304 patients with low- and intermediate-risk disease, Published: 10 January 2011 with favorable outcomes [11]. An update with 42 months median follow up was presented at ASTRO 2010 [33], References 1. Brenner DJ, Hall EJ: Fractionation and protraction for radiotherapy of and 5-year data from this study should be available in prostate carcinoma. Int J Radiat Oncol Biol Phys 1999, 43:1095-1101. 2011. An additional 114 low-intermediate risk prostate 2. Fowler JF, Ritter MA, Chappell RJ, Brenner DJ: What hypofractionated patients were treated with SBRT in Naples in 2006, so protocols should be tested for prostate cancer? 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Radiation OncologySpringer Journals

Published: Jan 10, 2011

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