Prostate Cancer Radiation
BIOCHEMICAL FAILURE AFTER RADIATION
The ASTRO consensus panel defined biochemical failure as three consecutive rises in PSA level after a nadir. The Phoenix definition of biochemical recurrence as a rise of greater than 2 ng/mL above the PSA nadir is a better predictor of clinical outcomes. (40)
EBRT
Up to 60% of men who receive EBRT for PCa have biochemical recurrence. (15,16) Conventional radiation is 39-40 doses at 78 to 80 Gy. Moderately hypofractionated is 20 doses at 60 Gy. A RCT of >1200 intermediate risk patients showed hypofractionated radiation is non-inferior to conventional doses. (17) DT + ERBT reaches PSA nadir <0.5ng/ml by 3 months compared to only 7% of ERBT or BT without ADT. (14)
HYPOFRACTIONATED
Conventional radiation is 39-40 doses at 78 to 80 Gy. Moderately hypofractionated is 20 doses at 60 Gy.A hypofractionated RT regimen in one trial was shown not inferior to conventional RT and was not associated with increased late toxicity. The authors find that hypofractionated RT is more convenient for patients and should be considered for intermediate-risk prostate cancer.(19)
BRACHYTHERAPY
A retrospective study of 2,339 low and intermediate risk prostate cancer (PCa) brachytherapy (BT) patients at 89 months found 86% had stable PSA, PSA rising in 6% and BCR in 8%. (1) Previous studies showed 93% to 95% long term DFS with BT. (2,3,4) PSA nadir is usually reached at 4 or 5 years post LDR BT. (5,6) Multiple groups have reported higher biochemical DFS (bDFS) and lower PCa specific mortality for BT (4,7,8,9) and EBRT (10) when PSA nadir is less than 0.5ng/ml. BT results in lower PSA levels compared to EBRT (0.04ng/ml vs. 0.62ng/ml) which correlated with 5 year bDFS (4) and a PSA nadir of 0.1ng/ml at 8 years for nonfailing LDR BT. (7) In about 40% of patients treated w/ BT, usually 12 to 24 months (but anytime between 3-30 months) there is a PSA benign rise after initial fall. (10) This is differentiated from failure in treatment which normally occurs 3 years after BT. (11) PSA doubling time of 3-6 months are at greater risk for distant metastasis or prostate cancer specific mortality (HR 19.6) (12, 13) ADT + ERBT reaches PSA nadir <0.5ng/ml by 3 months compared to only 7% of ERBT or BT without ADT. (14)
SIDE EFFECTS
A recent study of 84,397 patients showed increased bladder cancer (HR 1.35) in PCa patients treated w/ RT compared with RP. (20) In a meta-analysis of 5 RCT every 8-10 Gy increase in RT to prostate doubles the odds of severe late onset GI or GU toxicities and 63% increase in other toxicities. (21) Recent trials of modern RT show prostate RT results in late grade 2 or worse toxicities in rectum in 14-25% and 12-26% in GU. (22,23,24,25)
SPACERS
Spacers are placed transperineally between the prostate and rectum with the intended purpose of minimizing radiation associated rectal complications. Endorectal balloos have been trialed, but showed no dose sparing effect and can cause a shift in prostate location, decreasing efficacy of RT. (26,27,28) Transperineal injections of hyaluronic acid, blood patches and collagen have been tested and found to be well tolerated, easy to position and protective of rectum. (29,30,31,32) However, limitations such as to limited buffer space, material shift after placement or too rapid biodegradation have been identified. (33,34) Studies of off label injection of duraseal (polyethylene glycol (PEG) used as a spinal sealent) showed singificant rectal sparing during IMRT and low/high dose BT. (35,36)
Augmenix makes SpaceOAR which is a PEG based hydrogele spacer injected under US guidance. (37) Phase II trial shows at 12mo no grade 3-4 GI toxicities, 2.1% grade 3 GU toxicity and no grade 4 GU toxicity. Overall 4.3% GI toxicity (all grade I) were observed and late GU toxicity was 17% and 2.1%, 0%, 0% for grade 1, 2, 3 and 4 (38) and phase III study supported those results. (39) Space OAR should not be used with locally advanced advanced prostate cancer, in men with history of HIFU, cryo, RT, coagulopathies, on anticoagulation, patients with prostatities or inflammatory diseases (risk of ulceration, fistula, bleeding).
RT FOR METASTATIC PCa
A 2018 retrospective study of 64 patients with oligometastatic disease showed good results. (18)
The ASTRO consensus panel defined biochemical failure as three consecutive rises in PSA level after a nadir. The Phoenix definition of biochemical recurrence as a rise of greater than 2 ng/mL above the PSA nadir is a better predictor of clinical outcomes. (40)
EBRT
Up to 60% of men who receive EBRT for PCa have biochemical recurrence. (15,16) Conventional radiation is 39-40 doses at 78 to 80 Gy. Moderately hypofractionated is 20 doses at 60 Gy. A RCT of >1200 intermediate risk patients showed hypofractionated radiation is non-inferior to conventional doses. (17) DT + ERBT reaches PSA nadir <0.5ng/ml by 3 months compared to only 7% of ERBT or BT without ADT. (14)
HYPOFRACTIONATED
Conventional radiation is 39-40 doses at 78 to 80 Gy. Moderately hypofractionated is 20 doses at 60 Gy.A hypofractionated RT regimen in one trial was shown not inferior to conventional RT and was not associated with increased late toxicity. The authors find that hypofractionated RT is more convenient for patients and should be considered for intermediate-risk prostate cancer.(19)
BRACHYTHERAPY
A retrospective study of 2,339 low and intermediate risk prostate cancer (PCa) brachytherapy (BT) patients at 89 months found 86% had stable PSA, PSA rising in 6% and BCR in 8%. (1) Previous studies showed 93% to 95% long term DFS with BT. (2,3,4) PSA nadir is usually reached at 4 or 5 years post LDR BT. (5,6) Multiple groups have reported higher biochemical DFS (bDFS) and lower PCa specific mortality for BT (4,7,8,9) and EBRT (10) when PSA nadir is less than 0.5ng/ml. BT results in lower PSA levels compared to EBRT (0.04ng/ml vs. 0.62ng/ml) which correlated with 5 year bDFS (4) and a PSA nadir of 0.1ng/ml at 8 years for nonfailing LDR BT. (7) In about 40% of patients treated w/ BT, usually 12 to 24 months (but anytime between 3-30 months) there is a PSA benign rise after initial fall. (10) This is differentiated from failure in treatment which normally occurs 3 years after BT. (11) PSA doubling time of 3-6 months are at greater risk for distant metastasis or prostate cancer specific mortality (HR 19.6) (12, 13) ADT + ERBT reaches PSA nadir <0.5ng/ml by 3 months compared to only 7% of ERBT or BT without ADT. (14)
SIDE EFFECTS
A recent study of 84,397 patients showed increased bladder cancer (HR 1.35) in PCa patients treated w/ RT compared with RP. (20) In a meta-analysis of 5 RCT every 8-10 Gy increase in RT to prostate doubles the odds of severe late onset GI or GU toxicities and 63% increase in other toxicities. (21) Recent trials of modern RT show prostate RT results in late grade 2 or worse toxicities in rectum in 14-25% and 12-26% in GU. (22,23,24,25)
SPACERS
Spacers are placed transperineally between the prostate and rectum with the intended purpose of minimizing radiation associated rectal complications. Endorectal balloos have been trialed, but showed no dose sparing effect and can cause a shift in prostate location, decreasing efficacy of RT. (26,27,28) Transperineal injections of hyaluronic acid, blood patches and collagen have been tested and found to be well tolerated, easy to position and protective of rectum. (29,30,31,32) However, limitations such as to limited buffer space, material shift after placement or too rapid biodegradation have been identified. (33,34) Studies of off label injection of duraseal (polyethylene glycol (PEG) used as a spinal sealent) showed singificant rectal sparing during IMRT and low/high dose BT. (35,36)
Augmenix makes SpaceOAR which is a PEG based hydrogele spacer injected under US guidance. (37) Phase II trial shows at 12mo no grade 3-4 GI toxicities, 2.1% grade 3 GU toxicity and no grade 4 GU toxicity. Overall 4.3% GI toxicity (all grade I) were observed and late GU toxicity was 17% and 2.1%, 0%, 0% for grade 1, 2, 3 and 4 (38) and phase III study supported those results. (39) Space OAR should not be used with locally advanced advanced prostate cancer, in men with history of HIFU, cryo, RT, coagulopathies, on anticoagulation, patients with prostatities or inflammatory diseases (risk of ulceration, fistula, bleeding).
RT FOR METASTATIC PCa
A 2018 retrospective study of 64 patients with oligometastatic disease showed good results. (18)
- Tetreault-Laflamme, Audrey, et al. "Long-Term Prostate Specific Antigen Stability and Predictive Factors of Failure after Permanent Seed Prostate Brachytherapy." The Journal of urology 199.1 (2018): 120-125.
- Zelefsky, Michael J., et al. "Comparison of tumor control and toxicity outcomes of high-dose intensity-modulated radiotherapy and brachytherapy for patients with favorable risk prostate cancer." Urology 77.4 (2011): 986-990.
- Smith, Graham D., et al. "Brachytherapy improves biochemical failure–free survival in low-and intermediate-risk prostate cancer compared with conventionally fractionated external beam radiation therapy: A propensity score matched analysis." International Journal of Radiation Oncology• Biology• Physics 91.3 (2015): 505-516.
- Pickles, Tom, Mira Keyes, and W. James Morris. "Brachytherapy or conformal external radiotherapy for prostate cancer: a single-institution matched-pair analysis." International Journal of Radiation Oncology• Biology• Physics76.1 (2010): 43-49.
- Critz, Frank A. "Time to achieve a prostate specific antigen nadir of 0.2 ng./ml. after simultaneous irradiation for prostate cancer." The Journal of urology 168.6 (2002): 2434-2438.
- Pinkawa, Michael, et al. "Prostate-specific antigen kinetics following external-beam radiotherapy and temporary (Ir-192) or permanent (I-125) brachytherapy for prostate cancer." Radiotherapy and Oncology 96.1 (2010): 25-29.
- Zelefsky, Michael J., et al. "Multi-institutional analysis of long-term outcome for stages T1–T2 prostate cancer treated with permanent seed implantation." International Journal of Radiation Oncology• Biology• Physics 67.2 (2007): 327-333.
- Franca, Carlos Antônio da Silva, et al. "Relationship between two year PSA nadir and biochemical recurrence in prostate cancer patients treated with iodine-125 brachytherapy." Radiologia brasileira 47.2 (2014): 89-93.
- Huang, Shu-Pin, et al. "Significant associations of prostate-specific antigen nadir and time to prostate-specific antigen nadir with survival in prostate cancer patients treated with androgen-deprivation therapy." The Aging Male 15.1 (2012): 34-41.
- Crook, Juanita, et al. "PSA kinetics and PSA bounce following permanent seed prostate brachytherapy." International Journal of Radiation Oncology• Biology• Physics 69.2 (2007): 426-433.
- Ciezki, Jay P., et al. "PSA kinetics after prostate brachytherapy: PSA bounce phenomenon and its implications for PSA doubling time." International Journal of Radiation Oncology• Biology• Physics 64.2 (2006): 512-517.
- Zelefsky, Michael J., et al. "Outcome predictors for the increasing PSA state after definitive external-beam radiotherapy for prostate cancer." Journal of Clinical Oncology23.4 (2005): 826-831.
- D'AMICO, ANTHONY V., et al. "Prostate specific antigen doubling time as a surrogate end point for prostate cancer specific mortality following radical prostatectomy or radiation therapy." The Journal of urology 172.5 (2004): S42-S47.
- Pinkawa, Michael, et al. "Prostate-specific antigen kinetics after brachytherapy or external beam radiotherapy and neoadjuvant hormonal therapy." Urology 69.1 (2007): 129-133.
- Uddin Ahmed, Hashim, et al. "Whole‐gland salvage high‐intensity focused ultrasound therapy for localized prostate cancer recurrence after external beam radiation therapy." Cancer 118.12 (2012): 3071-3078.
- Agarwal, Piyush K., et al. "Treatment failure after primary and salvage therapy for prostate cancer." Cancer 112.2 (2008): 307-314.
- Catton, Charles N., et al. "Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer." Journal of Clinical Oncology 35.17 (2017): 1884-1890.
- Franzese, Ciro, et al. "The efficacy of Stereotactic body radiation therapy and the impact of systemic treatments in oligometastatic patients from prostate cancer." Cancer medicine (2018).
- Catton, Charles N., et al. "Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer." Journal of Clinical Oncology 35.17 (2017): 1884-1890.
- Moschini, Marco, et al. "External Beam Radiotherapy Increases the Risk of Bladder Cancer When Compared with Radical Prostatectomy in Patients Affected by Prostate Cancer: A Population-based Analysis." European urology(2018).
- Ohri, Nitin, Adam P. Dicker, and Timothy N. Showalter. "Late toxicity rates following definitive radiotherapy for prostate cancer." The Canadian journal of urology 19.4 (2012): 6373.
- Wortel, Ruud C., et al. "Late side effects after image guided intensity modulated radiation therapy compared to 3D-conformal radiation therapy for prostate cancer: results from 2 prospective cohorts." International Journal of Radiation Oncology* Biology* Physics 95.2 (2016): 680-689.
- Catton, Charles N., et al. "Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer." Journal of Clinical Oncology 35.17 (2017): 1884-1890.
- Dearnaley, David, et al. "Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: preliminary safety results from the CHHiP randomised controlled trial." The lancet oncology 13.1 (2012): 43-54.
- Aluwini, Shafak, et al. "Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial." The Lancet Oncology 17.4 (2016): 464-474.
- Serrano, Nicholas A., Noah S. Kalman, and Mitchell S. Anscher. "Reducing rectal injury in men receiving prostate cancer radiation therapy: current perspectives." Cancer management and research 9 (2017): 339.
- van Lin, Emile NJ Th, et al. "Rectal wall sparing effect of three different endorectal balloons in 3D conformal and IMRT prostate radiotherapy." International Journal of Radiation Oncology* Biology* Physics 63.2 (2005): 565-576.
- Jones, Bernard L., et al. "Effect of endorectal balloon positioning errors on target deformation and dosimetric quality during prostate SBRT." Physics in Medicine & Biology 58.22 (2013): 7995.
- Noyes, William R., Charles C. Hosford, and Steven E. Schultz. "Human collagen injections to reduce rectal dose during radiotherapy." International Journal of Radiation Oncology* Biology* Physics 82.5 (2012): 1918-1922.
- Morancy, T. J., et al. "Use of a blood-patch technique to reduce rectal dose during cesium-131 prostate brachytherapy." International Journal of Radiation Oncology• Biology• Physics 72.1 (2008): S331-S332.
- Prada, Pedro J., et al. "Transperineal injection of hyaluronic acid in anterior perirectal fat to decrease rectal toxicity from radiation delivered with intensity modulated brachytherapy or EBRT for prostate cancer patients." International Journal of Radiation Oncology* Biology* Physics 69.1 (2007): 95-102.
- Melchert, Corinna, et al. "Interstitial biodegradable balloon for reduced rectal dose during prostate radiotherapy: results of a virtual planning investigation based on the pre-and post-implant imaging data of an international multicenter study." Radiotherapy and Oncology 106.2 (2013): 210-214.
- Tang, Qiuying, et al. "The role of radioprotective spacers in clinical practice: a review." Quantitative imaging in medicine and surgery 8.5 (2018): 514.
- Hatiboglu, Gencay, et al. "Application technique: placement of a prostate–rectum spacer in men undergoing prostate radiation therapy." BJU international 110.11b (2012): E647-E652.
- Heikkilä, Vesa-Pekka, Aarno Kärnä, and Markku H. Vaarala. "DuraSeal® as a spacer to reduce rectal doses in low-dose rate brachytherapy for prostate cancer." Radiotherapy and Oncology 112.2 (2014): 233-236.
- Strom, Tobin J., et al. "A dosimetric study of polyethylene glycol hydrogel in 200 prostate cancer patients treated with high-dose rate brachytherapy±intensity modulated radiation therapy." Radiotherapy and Oncology 111.1 (2014): 126-131.
- FDA. De Novo Classification Request for SpaceOAR System: Decision Summary. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN140030.pdf. Accessed November 4, 2018.
- Uhl, Matthias, et al. "Absorbable hydrogel spacer use in men undergoing prostate cancer radiotherapy: 12 month toxicity and proctoscopy results of a prospective multicenter phase II trial." Radiation Oncology 9.1 (2014): 96.
- Mariados, Neil, et al. "Hydrogel spacer prospective multicenter randomized controlled pivotal trial: dosimetric and clinical effects of perirectal spacer application in men undergoing prostate image guided intensity modulated radiation therapy." International Journal of Radiation Oncology* Biology* Physics92.5 (2015): 971-977.
- Lee EK, Thrasher JB: Management of biochemical recurrence after definitive therapy for prostate cancer, in Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 3, chap 119, p 2778.