# Radiation Oncology/Prostate/External Beam RT

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## Historical Perspective

* EBRT as a curative treatment in localized prostate CA became generally accepted in 1950s with development of Cobalt_60 and linac megavoltage technologies. This was a dramatic change from prior kilovoltage therapies used for advanced cancer palliation, and allowed sufficient energy delivery to the prostate without significant toxicity to the skin.
** PMID 6020942 -- Radiotherapy in the conservative treatment of operable and locally inoperable carcinoma of the prostate. (1967 Del Regato JA., Radiology. 1967)
** PMID 14303057 -- Linear Accelerator Supervoltage Radiotherapy: VII. Carcinoma of the Prostate. (1965 Bagshaw MA, Radiology. 1965)
* RTOG 75-06 established 70 Gy as the maximum tolerable dose, beyond which significant GI toxicity (diarrhea) developed. The dose was given as 1.8-2.0 Gy/fx x5 days per week to 45-50 Gy either to whole pelvis or to prostate only, followed by a prostate only boost using same fractionation to 20 Gy.
* Treatment fields were generally 6x6 cm up to 11x11 cm "four-field box" determined by bony landmarks, and if necessary rectal contrast and foley catheter. For large fields, the superior border was set midway through the SI joint, inferior border at the level of ischial tuberosities, the lateral border 1.5-2.0cm lateral to the pelvic rim, the anterior border at the front edge of pubic symphisis, and the posterior border at the S2/S3 interspace. For small fields and boost, the superior border extended to the top of the acetabulum and laterally to include 2/3 of the obturator foramen. The fields were shaped by corner blocks only. However, reconstruction of these standard fields using CT imaging shows they may not cover tumors that were bulky, locally advanced or invading seminal vesicles.
** PMID 11146903 -- External beam radiation therapy for prostate cancer. (2000 Horwitz EM, CA Cancer J Clin. 2000)
** PMID 7939749 -- The biological basis and clinical application of three-dimensional conformal external beam radiation therapy in carcinoma of the prostate. (1994 Leibel SA, Semin Oncol. 1994)
* The 5-year clinical control rates were 70-90%; the biochemical disease-free survival (bNED) was ~60% (see below). Unfortunately, the outcomes for locally advanced (T3) disease were much worse, with 5-year outcomes <50%.
* There are several reasons for the relatively poor outcomes of conventional 2D RT:
** Presence of conventional radiation-resistant clones
** Inability of conventional planning techniques to deliver prescribed dose throughout tumor volume
** Uncertainities in patient positioning, requiring large safety margins to insure tumor coverage and resulting in significant RT doses to the bladder and rectum
* Two potential strategies were pursued to improve cure rates for higher risk patients: 1) increase the RT dose delivered to prostate to kill presumably radiation-resistant clones and 2) add androgen suppression to destroy androgen-dependent micrometastases outside of the PTV field
* For developments with androgen suppression, please see the Hormones page
* Several retrospective studies demonstrated that tumor control is related to dose level, and that doses necessary for local control exceed the 70 Gy maximum tolerated dose
** PMID 3198435 -- The effect of dose on local control of prostate cancer. (1988 Hanks GE, Int J Radiat Oncol Biol Phys. 1988)
** PMID 10386637 -- Conventional external-beam radiation therapy alone or with androgen ablation for clinical stage III (T3, NX/N0, M0) adenocarcinoma of the prostate. (1999 Zagars GK, Int J Radiat Oncol Biol Phys. 1999)
** PMID 10894874 -- Survival advantage from higher-dose radiation therapy for clinically localized prostate cancer treated on the Radiation Therapy Oncology Group trials. (2000 Valicenti R, J Clin Oncol. 2000)
* The development of CT and computer-driven planning programs in the mid 1980's led to the development of 3D-CRT at University of Michigan, which allows to more precisely target radiation delivery. The minimization of rectal and bladder volumes included in high-dose regions thus permits an escalation in the tumor dose without concurrent increase in toxicity, and will hopefully improve the probability of local cure.
** PMID 2492268 -- Boost treatment of the prostate using shaped, fixed fields. (1989 Ten Haken RK,Int J Radiat Oncol Biol Phys. 1989 Jan;16(1):193-200.)
** PMID 7939749 -- The biological basis and clinical application of three-dimensional conformal external beam radiation therapy in carcinoma of the prostate. (1994 Leibel SA, Semin Oncol 1994; 21:580-97.)
* University of Michigan, Memorial Sloan Kettering, Fox Chase, and MD Anderson pioneered sequential dose escalation from 70 Gy to 80+ Gy. Based on their early results, RTOG sponsored a 3D-CRT dose escalation trial 94-06 in 1994. Its successful conclusion led to the initiation of a Phase III randomized trial 01-26 comparing 70.2 Gy vs 79.2 Gy, which is ongoing.
* Meanwhile, the 3D-CRT technique has been further modified to include intensity modulation (IMRT) of the treatment beams using multi-leaf collimators in a dynamic mode (in motion during radiation delivery). This provides improved conformality and increased dose homogeneity in the planning target volume. While acute toxicity appears better than in 3D-CRT, outcome reports are as yet lacking.
** PMID 8690638 -- Conformal radiation treatment of prostate cancer using inversely-planned intensity-modulated photon beams produced with dynamic multileaf collimation. (1996 Ling CC, Int J Radiat Oncol Biol Phys 1996; 35:721-30.)

## Field Size

Conventional (2D) Technique
* Treatment fields are generally "four-field box" determined by bony landmarks, and if necessary rectal contrast and foley catheter.
* For large fields, the superior border is set midway through the SI joint, inferior border at the level of ischial tuberosities, the lateral border 1.5-2.0cm lateral to the pelvic rim, the anterior border at the front edge of pubic symphisis, and the posterior border at the S2/S3 interspace.
* For small fields and boost, the superior border extends to the top of the acetabulum and lateraly to include 2/3 of the obturator foramen.
* However, reconstruction of these standard fields using CT imaging shows they may not cover tumors that are bulky, locally advanced or invading seminal vesicles.

### Para-aortic

* RTOG 75-06 (1976-1983)
** Randomized. 523 patients with clinical Stage A2-B N+ or Stage C. Arm 1) Pelvic RT 40-45 Gy + prostate boost 20-25 Gy (minimum 65 Gy) vs. Arm 2) Pelvic + PA RT 40-45 Gy + prostate boost (minimum 65 Gy)
** 1986 PMID 3514555 -- "Extended field (periaortic) irradiation in carcinoma of the prostate--analysis of RTOG 75-06." (Pilepich MV, Int J Radiat Oncol Biol Phys. 1986 Mar;12(3):345-51.). Median F/U 4.2 years
*** Outcome: No difference between arms for DFS, DM, OS
*** Toxicity: Periaortic RT does not increase bowel injury. Prostate doses >70Gy result in increased bowel injury (20% vs 10% rectal bleed) but not bladder injury
*** Conclusion: No benefit to elective peri-aortic irradiation

### Pelvic

Randomized
* GETUG-01 (French)(1998-2004)
** Randomized. 444 patients, T1b-T3 N0 pNx. Randomized to Arm 1) prostate + pelvis vs. Arm 2) prostate only. RT dose pelvis 46 Gy and prostate 66-70 Gy. Stratified into low (T1-2 and GS <=6 and PSA <=12), intermediate, and high risk (T3 or GS >=7 or PSA >=12 ng/ml; 79%) groups. Short term hormonal therapy (6 mos) allowed only for high risk group.
** 5-years; 2007 PMID 18048817 — "Is There a Role for Pelvic Irradiation in Localized Prostate Adenocarcinoma? Preliminary Results of GETUG-01." Pommier P et al. J Clin Oncol. 2007 Dec 1;25(34):5366-5373. Median F/U 3.5 years
*** 5-year outcome: PFS 66% vs. 65% (NS); high risk PFS 63% vs. 60% (NS); low risk PFS 75% vs. 84% (NS)
*** Toxicity: Pelvic arm small but nonsignificant late GI toxicity
*** Conclusion: no benefit to pelvic radiotherapy
** Comment (Nguyen/D'Amico 2008, PMID 18421061): Two randomized trials (94-13 and GETUG-01) have both shown no benefit for pelvic RT. Therefore, evidence is lacking for using pelvic fields in intermediate- and high-risk PCA. Suggest randomized trial for T3/T4 and GS >=4+3
** Comment (Roach 2008, PMID 18669477): Based on the data, the burden of proof to not use WPRT on those who choose not to use it.
** Comment (Nguyen/D'Amico 2008, same PMID 18669477 link): Given the potential toxicity, and the negative results of the two trials, it is difficult to justify WPRT for the type of men studied in RTOG 94-13 and GETUG 01
* RTOG 94-13 (1995-99)
** Randomized. 1323 patients. High risk patients with estimated risk of LN involvement of 15% or more by the Roach equation and PSA < 100. Pts with T2c-T4 tumors and Gleason >=6 were allowed regardless of LN risk. 2x2 randomization. Randomized to whole-pelvic (WP) vs prostate-only (PO) RT, and combined neoadjuvant + concurrent hormonal therapy (NCHT) vs adjuvant hormonal therapy (AHT).
** Hormones: For NCHT, total of 4 months - 2 months before and 2 months during RT. For AHT, began following RT for total of 4 months. RT: Dose 70.2 Gy to prostate. For WP RT, 50.4 Gy to pelvis (16x16 field), followed by boost to prostate only. PO RT was to prostate + SV only.
** 2003 PMID 12743142, 2003 — "Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413." (Roach M et al. J Clin Oncol. 2003 May 15;21(10):1904-11.). Median F/U 5 years
*** Outcome: 4-year PFS WP 54% vs PO 47%. No difference for NCHT vs AHT (52% vs 49%). Improved PFS for WP + NCHT vs other arms. No OS difference
** 5-years; 2005: ASTRO 2005 (Abstract) — "An Update of the Phase III Trial Comparing Whole-Pelvic (WP) to Prostate Only (PO) Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression (TAS): Updated Analysis of RTOG 94-13." Lawton CA et al. IJROBP Volume 63, Supplement 1, 1 October 2005, Page S19. Median F/U 5.9 years
*** Outcome: 5-yr PFS 48.3% (WP/NHT), 36.8% (PO/NHT), 38.1% (WP/AHT), 40.4% (PO/AHT). Pairwise: WP/NHT > PO/NHT (SS), WP/NHT > WP/AHT (p=0.06). No difference in survival. 5-yr biochemical failure 35.9%, 45.5%, 42.8%, and 40.0%.
*** Conclusion: Improved PFS for whole pelvic treatment and for neoadjuvant hormones for high risk patients.
** "Mini pelvis; 2006" - PMID 17011443, 2006 — "Whole-pelvis, "mini-pelvis," or prostate-only external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in patients treated in the Radiation Therapy Oncology Group 9413 trial." Roach M et al. Int J Radiat Oncol Biol Phys. 2006 Nov 1;66(3):647-53.
*** Subset analysis in patients with N&CHT hormones (WP+NCHT n=325, PO+NCHT n=324). "Mini pelvis" were defined as those randomized to prostate only RT who had a field size > median size of 10 x 11 cm, while "prostate only" had median size field <10x11 cm.
*** Outcome: Median PFS 5.2 (WP), 3.7 (MP), and 2.9 yrs (PO).
*** Conclusion: In patients with neoadjuvant+concurrent RT, increasing field size appears to have impact on PFS
*** Editorial: JCO - Correspondence: "In reply." Roach M. J Clin Oncol, Vol 22, No 11 (June 1), 2004: pp. 2255-2257.
** 7-years; 2007 PMID 17531401 -- "An Update of the Phase III Trial Comparing Whole Pelvic to Prostate Only Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression: Updated Analysis of RTOG 94-13, With Emphasis on Unexpected Hormone/Radiation Interactions." (Lawton CA, Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):646-55.) Median F/U for alive patients 7.0 years
*** Outcome: PFS WPRT+NHT 62% vs. PORT+NHT 66% vs. WPRT+AHT 69% vs. PORT+AHT 62% (NS); also no difference in OS. By pairs, no difference between WPRT and PORT, and no difference between NHT and AHT. No difference in LF or DM
*** Toxicity: No difference in RT Grade 3+ toxicity among the 4 arms
*** Conclusion: No benefit for NHT + WPRT compared with PORT + AHT
** Comment: the benefit of neoadjuvant hormones combined with irradiation to the pelvic lymph nodes implies that the benefit of hormones is in increasing the effectiveness of RT on the lymph nodes (which receive low dose RT) vs that of increasing local control in the prostate which receives a high dose of RT.
* RTOG 77-06 (1978-1983) - Whole pelvis vs prostate only RT
** Randomized. 445 patients. Prostate cancer, Stage A2 (disease on TRUP, poorly differentiated) and Stage B (N0 by lymphangiogram or biopsy). Arm 1) Prostate only 65 Gy vs. Arm 2) Pelvis 45 Gy + prostate boost 20 Gy.
** 1988 PMID 3058656 -- "Elective pelvic irradiation in stage A2, B carcinoma of the prostate: analysis of RTOG 77-06." (Asbell SO, Int J Radiat Oncol Biol Phys. 1988 Dec;15(6):1307-16.) Median F/U 7 years
*** Outcome: No difference in terms of LC, DM, DFS, OS.
*** Conclusion: No significant benefit for elective pelvic irradiation
*** Critique: included pts at low risk for LN involvement
Retrospective
* Italy (Rome) (1994-2007) - Long term ADT; Pelvis vs Prostate Only
** Retrospective. 358 high risk pts (T2c-T4, or G7-10, or PSA>20). Treated to pelvis + prostate, but pts deemed at risk for increased GI toxicity (those with inflammatory bowel disease, or diverticulosis/itis) were treated to prostate/SV only (PORT). 45 Gy to the pelvis; 70.2-73.8 Gy to the prostate. ADT began 2 months prior to RT, median duration 24 months.
** 46.9% treated with WPRT and 53.1% with PORT. Stratified by nodal involvement risk using Roach formula (cutoffs >15, >20, >25, >30).
** 2011 PMID 21277100 -- "Effect of whole pelvic radiotherapy for patients with locally advanced prostate cancer treated with radiotherapy and long-term androgen deprivation therapy." (Mantini G, Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):e721-6.)
*** Median f/u 52 months. 4-yr bDFS 90.4 (WPRT) vs 90.5% (PORT). By nodal involvement risk, bDFS was improved in those with the greatest risk (>30): 87.9 (WPRT) vs 70.4% (PORT); SS. Trend for those with nodal risk >25: 86.8% vs 69.0% (p=0.07).
*** Conclusion: "Our analysis has supported the use of WPRT in association with long-term ADT for patients with high-risk nodal involvement (>30%), although a definitive recommendation should be confirmed by a randomized trial."
* University of Michigan; 2008 (1987-2005) PMID 18308110 -- "Impact of common iliac nodal treatment on radiation outcomes in localized prostate cancer." (Soto DE, Urology. 2008 Feb;71(2):313-7.)
** Retrospective. 669 patients with T1-T3 CaP, treated with 3D-CRT to whole pelvis (42%) or minipelvis (57%). Low risk 11%, intermediate risk 35%, high risk 54%. Median WP dose 71 Gy, MP 75 Gy. ADT 36%, 52%. Median F/U 4.7 years
** Outcome: 5-year bPFS MP 73% vs WP 58% (NS on MVA)
** Conclusion: No difference between patients undergoing WP vs MP
* Multinational, retrospective, 2005 (1986-2003) - PMID 15964706 — "Lack of benefit of pelvic radiation in prostate cancer patients with a high risk of positive pelvic lymph nodes treated with high-dose radiation." Vargas CE et al. Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1474-82.
** Purpose: to determine the need to treat the pelvic lymph nodes in pts with LN risk of >15%
** Retrospective review of 1491 pts treated at 3 centers in the USA and Germany. Pts were stratified into groups depending on the calculated risk of LN involvement by the Roach equation: Group I, <15%; Group II, 15-30%; Group III, >30%. Pts were treated with EBRT and brachytherapy. 596 pts had >15% risk. Of these, the pelvis was treated at two centers (312 pts) and was not treated the third center (284 pts). 42% of pts received hormonal therapy for <=6 months.
** Median f/u 4 yrs for all pts, 4.3 yrs for those high risk pts. For the high risk pts, there was no difference in clinical failure, CSS, or OS.
** Comment: Biochemical failure was not specified and may be important with longer follow-up.
Seminal vesicles:
* William Beaumont Hospital, 2002 - PMID 12377319 — "Treatment of prostate cancer with radiotherapy: should the entire seminal vesicles be included in the clinical target volume?" Kestin L et al. Int J Radiat Oncol Biol Phys. 2002 Nov 1;54(3):686-97.
** Studied prostatectomy specimens and measured the length of SV invasion
** Median length of SV involvement 1.0 cm; 90th percentile, 2.0 cm; median of 25% of length of SV was involved.
** Conclusion: when treating the SV for prostate cancer, only the proximal 2.0-2.5 cm (approximately 60%) of the SV should be included within the CTV.

## Prostate Localization

Change in prostate location between dose fractions can be significant. Displacement is greatest in the AP direction, where it can reach 2+ cm, and is correlated with rectal and bladder filling. Given that 3D-CRT/IMRT PTV margins are typically 0.5-1 cm posteriorly to avoid unacceptable rectal dose and that many PCAs are located in the posterior zone, there is a significant risk of geographical miss upon prostate motion. Consistent (preferably empty) rectum and bladder during simulation and treatment, as well as daily verification of prostate location may decrease the risk of geographical miss and improve outcomes.
* Princess Margaret; 2008 PMID 18279985 -- "A randomized comparison of interfraction and intrafraction prostate motion with and without abdominal compression." (Rosewall T, Radiother Oncol. 2008 Feb 13 [Epub ahead of print])
** Randomized. 32 patients. Arm 1) VacLok immobilization vs. Arm 2) BodyFix adbominal compression. Interfraction motion >3 mm corrected pre-treatment.
** Outcome: No difference in interfraction or intrafraction motion with or without adnominal compression
** Conclusion: Addition of abdominal compression didn't influence interfraction or intrafraction prostate motion
* MD Anderson; 2007 PMID 17892900 -- "Is a 3-mm intrafractional margin sufficient for daily image-guided intensity-modulated radiation therapy of prostate cancer?" (Melancon AD, Radiother Oncol. 2007 Nov;85(2):251-9. Epub 2007 Sep 24.)
** Prospective. 46 patients. CT scan acquired prior and after fraction. Pre-fraction IMRT plan recalculated on post-fraction CT
** Outcome: Median reduction in prescribed dose for prostate 0.1% and SV 1.0%; and minimum dose 0.5 Gy and 1.5 Gy. Three prostates and 8 SVs did not maintain coverage >70 Gy. Rectal filling correlated with decreased coverage
** Conclusion: 3 mm intrafraction margin adequate for prostate coverage but not SV coverage

### Prostate location variability

Marker implantation:
* UCSF PMID 14529767 -- Evaluation of ultrasound-based prostate localization for image-guided radiotherapy. (2003 Langen Int J Radiat Oncol Biol Phys 2003; 57:635-44.)
** Daily BAT U/S measurements compared to implanted markers
** Markers: AP -0.9 +/- 3.9mm (posteriorly), SI 0.1 +/- 3.9mm, LR and 0.2 +/- 3.4mm
** BAT: BAT alignments were systematically different from the marker alignments in the superoinferior, and lateral directions. The remaining random variability of the prostate position after the ultrasound-based alignment was similar to the initial variability. However, the occurrence of displacements >/=5 mm was reduced in the AP direction.
* Michigan PMID 7995741 -- Measurement of prostate movement over the course of routine radiotherapy using implanted markers. (1995 Balter JM, Int J Radiat Oncol Biol Phys; 31:113-8.)
** Translation and/or rotation of the prostate was detected in 70% of the treatments. Maximum displacement was 7.5 mm; typical translations were between 0-4 mm.
** Conclusion: "Although significant prostate displacement can occur between treatments, the typical range of movement seen along a major axis was less than 5 mm. Proper treatment planning should consider the movement of the target independent of surrounding bony anatomy."
* Ottawa PMID 8539455 -- Prostate motion during standard radiotherapy as assessed by fiducial markers. (1995 Crook JM, Radiother Oncol; 37:35-42.)
** The base of the prostate was displaced more than 1 cm posteriorly in 30% of patients and in 11% in the inferior direction.
** Conclusion: "Changes in prostate position of this magnitude preclude the use of standard margins."
CT scan:
* MSKCC PMID 10368047 -- Quantification and predictors of prostate position variability in 50 patients evaluated with multiple CT scans during conformal radiotherapy. (1999 Zelefsky MJ, Radiother Oncol 1999; 50:225-34.)
** Mean prostate displacement AP -1.2 +/- 2.9 mm (posteriorly), SI -0.5 +/- 3.3 mm (inferiorly), and -0.6 +/- 0.8 mm (right)
** Mean SV displacement: AP - 1.4 +/- 4.9 mm (posteriorly), SI 1.3 +/- 5.5 mm (superiorly), and -0.8 +/- 3.1 (right)
** AP movement of both the prostate and seminal vesicles were correlated with changes in rectal volume (P = 0.0014 and < 0.0001, respectively) more than with changes in bladder volume (P = 0.030 for seminal vesicles and 0.19 for prostate). A logistic regression analysis identified the combination of rectal volume > 60 cm3 and bladder volumes > 40 cm3 as the only predictor of large ( > 3 mm) systematic deviations for the prostate and seminal vesicles (P = 0.05)
** Conclusion: "Prostatic displacement during a course of radiotherapy is more pronounced among patients with initial planning scans with large rectal and bladder volumes. Such patients may require more generous margins around the CTV to assure its enclosure within the prescription dose region."
* MDACC PMID 9806528 -- Prostate target volume variations during a course of radiotherapy. (1998 Antolak JA, Int J Radiat Oncol Biol Phys; 42:661-72.)
** CT scan at plan, then 3 follow-on q 2 weeks
** The mobility of the CTV was characterized by standard deviations of 0.09 cm (left-right), 0.36 cm (cranial-caudal), and 0.41cm (anterior-posterior).
** Mobility of both the prostate and seminal vesicles was very significantly correlated with rectal volume.
** Conclusion: "Margins between the CTV and PTV based on the simple geometric requirement that a point on the edge of the CTV is enclosed by the PTV 95% of the time are 0.7 cm in the lateral and cranial-caudal directions, and 1.1 cm in the anterior-posterior direction. However, minimum dose to the CTV and avoidance of organs at risk are more important considerations when drawing beam apertures. More consistent methods for reproducing prostate position (e.g., empty rectum) and more sophisticated beam aperture optimization are needed to guarantee consistent coverage of the CTV while avoiding organs at risk."
* JCRT PMID 8567348 -- Analysis of prostate and seminal vesicle motion: implications for treatment planning. (1996 Beard CJ, Int J Radiat Oncol Biol Phys 1996; 34:451-8.)
** The distribution of positional changes were generally small (< 0.5 cm), but maximum displacements of 1.5-2.2 cm did occur
** Bladder volume changes between the scans were small and did not correlate with target motion (P = 0.67)
** Both rectal volume and rectal diameter changes correlated with target motion for both the prostate (p = 0.004 and 0.005, respectively) and seminal vesicles (p < 0.001 and < 0.001, respectively).
** Conclusion: "Target motion occurs during the course of treatment planning and delivery and should be considered when designing conformal radiation fields."
* Chicago PMID 7493857 -- Evaluation of changes in the size and location of the prostate, seminal vesicles, bladder, and rectum during a course of external beam radiation therapy. (1995 Roeske Int J Radiat Oncol Biol Phys 1995; 33:1321-9.)
** Center-of-mass (CM) showed motion of less than 1 mm in the left-right direction, while motion ranging from 0 to +/- 1 cm was observed in the anterior-posterior and superior-inferior directions.
** Conclusion: "Changes in the location of the prostate, seminal vesicles, and normal tissue volumes during the course of radiation therapy occur and have dosimetric consequences that may impact tumor control and normal tissue complication probabilities."
Ultrasound:
* MDACC PMID 12738318 -- Experience of ultrasound-based daily prostate localization. (2003 Chandra A, Int J Radiat Oncol Biol Phys 2003; 56:436-47.)
** Daily BAT U/S measurements
** Interfraction 1 SD was AP 4.9mm, SI 4.4mm, and LR 2.8mm
** % of BAT where shift was >5mm (potential to violate PTV):AP 29%, SI 23%, LR 9%
** Conclusion: "Although the accuracy of the BAT was not addressed in this investigation, we found a significant percentage of large shifts being made from the initial alignment position."

### Intrafraction motion

* MD Anderson; 2008 PMID 18280057 -- "Observations on real-time prostate gland motion using electromagnetic tracking." (Langen KM, Int J Radiat Oncol Biol Phys. 2008 Jul 15;71(4):1084-90. Epub 2008 Feb 14.)
** Prospective. 17 patients, tracked with Calypso, 550 continuous tracking sessions
** Outcome: Average displacement >3 mm in 14%, >5 mm in 3% of total treatment time. For individual patients, 36% and 11%. For individual fractions, 99% and 99%. Displacements increased with elapsed time from set-up
** Conclusion: Prostate displacement intra-fraction determined
* U. Michigan; 2005 ASTRO 2005 Abstract #7 - no PMID Webcast — "The Influence of Intrafraction Movement on Margins for Prostate Radiotherapy." Litzenberg DG et al. IJROBP Volume 63, Supplement 1, 1 October 2005, Page S4.
** Used Calypso System that continuously tracks implanted markers. 3 markers placed in each prostate of 11 pts. Pts monitored for 8 mins.
** If based on skin marks alone, required margins (avg.) of 8.0 mm left-right, 7.3 mm A-P, and 10.0 mm C-C (without intrafraction motion), or 8.2, 10.2, and 12.5 mm (including intrafraction motion). Positioning by prostate markers at the start of treatment reduced margins to 1.8, 5.8, and 7.1 mm. Interbeam adjustment reduced to 0.4, 2.3, 1.8 mm. Using intrafractional adjustment, reduced to 0.3, 1.5, and 1.5 mm.

### Prostate location and outcome

* MDACC PMID 15989996 -- "Increased risk of biochemical and local failure in patients with distended rectum on the planning CT for prostate cancer radiotherapy." (de Crevoisier R, Int J Radiat Oncol Biol Phys. 2005 Jul 15;62(4):965-73.)
** Retrospective review of 127 patients treated with 3D-CRT to 78Gy
** Patients with distended rectum on planning CT had significantly worse PSA control (p=0.0009) than those with normal rectum. Rectal distention had greater impact on outcome (HR=3.89) than high risk disease (HR=2.45)
** Conclusion: "We found strong evidence that rectal distension on the treatment-planning CT scan decreased the probability of biochemical control, local control, and rectal toxicity in patients who were treated without daily image-guided prostate localization, presumably because of geographic misses. Therefore, an empty rectum is warranted at the time of simulation."
See also: Radiation_Oncology/Prostate/Adjuvant_RT#Organ motion

## Dose escalation

Please see complete information at the Dose Escalation page

## Hypofractionation

* Please also see the Hypofractionation page
* Please also see post-prostatectomy hypofractionation section

## 3D-CRT

3-dimensional conformal radiotherapy
* ASTRO review, 2005: PMID 15850897 — "Evidence-based review of three-dimensional conformal radiotherapy for localized prostate cancer: an ASTRO outcomes initiative." Morris DE et al. Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):3-19.

## IMRT

Prostate IMRT Page

## Treatment time

* Fox Chase; 2008 (1989-2004) PMID 18472368 -- "Does Treatment Duration Affect Outcome After Radiotherapy for Prostate Cancer?" (D'Ambrosio DJ, Int J Radiat Oncol Biol Phys. 2008 May 7. [Epub ahead of print])
** Retrospective. 1796 men treated with RT alone. Median RT dose 76 Gy. Non-treatment day ratio (NTDR) defined as number of nontreatment days divided by total elapsed days. If no break, NTDR = 26% for 40 fraction treatment. Stratified into low risk, intermediate risk, and high risk
** Outcome: 10-year bPFS NTDR <33% 68% vs. >33% 58% (SS). If low risk, 82% vs. 57% (SS), if intermediate/high risk no difference. Independently predictive of bPFS on multivariate analysis
** Conclusion: Longer treatment duration an adverse factor in low risk patients. NTDR >=33% (4+ treatment breaks during 40 fraction treatment) should be avoided
* Abstract — "The effect of overall treatment time on the outcome of definitive radiotherapy for localized prostate carcinoma: the Radiation Therapy Oncology Group 75-06 and 77-06 experience." Lai et al.
    No difference for <7wks vs >9wks. (This was pre-PSA era.)

## Do long-term survivors have a biochemical cure?

* Abstract — "PSA confirmation of cure at 10 years of T1B, T2, N0, M0 prostate cancer patients treated in RTOG protocol 7706 with external beam irradiation." Hanks et al.
    Yes. 17 survivors at 10 years with no evidence of disease had PSA tested. 88% had PSA < 3.5.

## Outcomes

Also please see Outcomes in the Localized Prostate Cancer section
* Shipley et al, "Gang of Six" - Abstract Full Text — "Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis." Shipley WU et al. JAMA. 1999 May 5;281(17):1598-604.
** 8 institutions, 1765 pts, T1b-T2NxM0, treated between 1988-95, EBRT alone, androgen therapy not allowed. Median PSA 10. Required baseline PSA and 4+ post-XRT PSA measurements. Median f/u 4 years.
* Kuban et al - Abstract — "Long-term multi-institutional analysis of stage T1-T2 prostate cancer treated with radiotherapy in the PSA era." Kuban DA et al. Int J Radiat Oncol Biol Phys. 2003 Nov 15;57(4):915-28.
** 9 institutions, 4839 pts, T1b-T2N0, treated between 1986-95, EBRT alone to dose > 60 Gy, no hormonal therapy (until biochemical failure), median f/u 6 years.
* Mass General - 1044 men, 1997-1991, T1-4NxM0
    10-years, 40% of T1-2 disease free. By grade, Grade 1-2: 53% DFS; Grade 3:42%; Grade 4-5:20%. T3-4: 18% overall.
    Poor results with radiotherapy alone (low dose, no 3D-CRT)
** Abstact Zeitman et al.

## Outcome Prediction

After biochemical failure following treatment, predictors for distant metastases and death are PSA-DT, clinical stage, and biopsy Gleason score.
* MDACC, 2007 (1993-1998) - PMID 17161554 -- "The predictive value of 2-year posttreatment biopsy after prostate cancer radiotherapy for eventual biochemical outcome." Vance et al. Int J of Radiat Onc, Biol, Phys. 67(3):828-33, 2007 Mar 1.
** 164 pts who underwent a planned 2yr post-tx biopsy.
** Current nadir + 2 used as biochemical failure. Bx results divided into several categories: normal, scant atypical and malignant cells, carcinoma w/ tx effect, carcinoma w/o tx effect.
** Significant association b/w bx results and eventual biochemical failure.
* MSKCC PMID 15681527 -- Outcome predictors for the increasing PSA state after definitive external-beam radiotherapy for prostate cancer. (2005 Zelefsky MJ, J Clin Oncol.)
** 1,650 patients with T1-T3 treated with high-dose 3D-CRT; 381 patients developed PSA failure; median follow-up 92 months from completion of RT
** 5-year incidence of DM after an established PSA relapse was 29%
** PSA-DT (P < 0.001), clinical T stage (P < 0.001), and Gleason score (P = 0.007) independent predictors for DM after established biochemical failure
** PSA-DT for favorable (20.0 months), intermediate (13.2 mo), and unfavorable (8.2 mo) -risk patients **3-year incidence of DM for patients with PSA-DT of 0-3, 3-6, 6-12, 12+ months was 49%, 41%, 20%, and 7%, respectively (P < .001).
** Patients with PSA-DT of 0-3 and 3-6 months demonstrated a 7.0 DM hazard and 6.6 death hazard compared with PSA-DT 12+
** Conclusion: "In addition to clinical stage and Gleason score, PSA-DT was a powerful predictor of DM among patients who develop an isolated PSA relapse after external-beam radiotherapy for prostate cancer. Patients who develop biochemical relapse with PSA-DT < or = 6 months should be considered for systemic therapy or experimental protocols because of the high propensity for rapid DM development."
* Fox Chase; 2003 (1989-97) PMID 12569615 -- "Validation of a treatment policy for patients with prostate specific antigen failure after three-dimensional conformal prostate radiation therapy." (Pinover WH, Cancer. 2003 Feb 15;97(4):1127-33.) Median F/U 44 months.
** 248 pts with PSA failure (ASTRO definition). Treated 1989-97 with definitive RT, median 74 Gy. Per policy, pts were treated with hormonal therapy for PSA failure if PSA doubling time < 12 months; for PSA doubling time > 12 months, observation without treatment. Endpoints were measured from time of PSA failure (midpoint between PSA nadir and first rise in PSA).
** Of pts with PSA-DT <12 months (148), 40%(59) were treated with immediate AD, 60% refused. Pts with PSA-DT >12m (100), 89% were observed, 11% started immediate AD.
** 47 pts had DM. For those with short PSA-DT, improved 5-yr FDM (78% v 57%) if treated with AD. Median time to DM: 25 months vs 6 months. For long PSA-DT, no sig diff in FDM (88% v 92%) with AD. 86% of pts who achieved PSA nadir < 1.5 were free of DM, vs 50% who did not.
** Conclusion: pts with PSA-DT < 12 months benefit from immediate AD

## Effect of RT on testosterone

* British Columbia, 2002 - PMID 11992055 — "What happens to testosterone after prostate radiation monotherapy and does it matter?" Pickles T et al. J Urol. 2002 Jun;167(6):2448-52.
** 666 men received RT without androgen ablation. Testosterone and PSA were measured every 3-6 months.
** Testosterone decreased by to an avg of 83% of baseline at a median nadir of 6 months; 7.5% fell to < 50%. 97% returned to normal levels but only 60% returned to their baseline. No correlation with biochemical control.

## Toxicity

Acute toxicity appears to depend primarily on volume treated, more than DVH. Efforts to reduce toxicity currently proceed along 3 lines:
* Exclusion of seminal vesicles or treatment of only proximal 2 cm in appropriately selected patients
* Reduction of margins with improved daily positioning (U/S, CT, fiduciary markers)
* Pre-reduction of prostate volume using neoadjuvant hormone therapy
** PMID 9123735 -- Neoadjuvant androgen ablation prior to radiotherapy for prostate cancer: reducing the potential morbidity of therapy. (1997 Zelefsky MJ, Urology 1997; 49:38-45.). Conclusion: "Neoadjuvant hormonal therapy effectively reduces the volume of normal tissue exposed to high radiation doses in the majority of treated patients and decreases the potential morbidity of therapy."
* William Beaumont, 2005 (1999-2002) PMID 16111582 -- "Phase II dose escalation study of image-guided adaptive radiotherapy for prostate cancer: use of dose-volume constraints to achieve rectal isotoxicity." (Vargas C, Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):141-9.)
** Phase II. 331 patients with cT1-T3N0. RT constraints: 1) <30% of rectal wall >75.6 Gy, and 2) <5% of rectal wall >82 Gy. Doses 72, 73.8, 75.6, 77.4 and 79.2 Gy. Median F/U 1.6 years
** Toxicity: 2-year late Grade 3+ rectal toxicity 3%, Grade 2+ 17%. No difference by dose level
** Intermediate group (Prostate + SV) worse chronic rectal bleeding (17%) vs. low-risk group (Prostate only) 8% (SS)
** Conclusion: high dose (79.2 Gy) safely delivered by adaptive RT process. Larger PTV increases rectal wall dose and chronic toxicity
* MDACC PMID 14630260 -- Hazards of dose escalation in prostate cancer radiotherapy. (2003 Kuban D, Int J Radiat Oncol Biol Phys 2003; 57:1260-8.)
** Conclusion: "In intermediate- and high-risk prostate cancer patients, although it appears that radiation-dose escalation may improve PSA-DF outcome, the price paid in treatment morbidity can be high without adequate attention to dose-volume constraints of normal tissue. Care must be taken to consider not only the hazard of tumor recurrence but also that of complications."
* PMID 12459352 -- Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer. (2002 Huang EH, Int J Radiat Oncol Biol Phys. 2002)
** 163 T1b-T3c patients treated 1992-1999 with 3D-CRT, to a total isocenter dose of 74-78 Gy at MDACC; median follow-up was 62 months (range 24-102).
** 6-year Grade 2+ late rectal toxicity rate was 25%
** Conclusion: "Dose-volume histogram analyses clearly indicated a volume effect on the probability of developing late rectal complications. Therefore, dose escalation may be safely achieved by adherence to dose-volume histogram constraints during treatment planning and organ localization at the time of treatment to ensure consistent patient setup."
* PMID 11172950 -- Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms. (2001 Jackson A, Int J Radiat Oncol Biol Phys. 2001)
** Average DVH for the rectal wall of patients with bleeding was significantly higher than DVH of patients without bleeding in both (70.2 Gy or 75.6 Gy) dose groups (p = 0.02, 70.2 Gy; p < 0.0001, 75.6 Gy).
** Conclusion: "Significant volume effects were found in the probability of late rectal bleeding for patients undergoing 3D-CRT for prostate cancer with prescription doses of 70.2 and 75.6 Gy. The percent volumes exposed to 71 and 77 Gy in the 70.2 and 75.6 Gy dose groups respectively were significantly correlated with rectal bleeding. The independent correlation of small V(RW) with rectal bleeding may indicate the existence of a functional reserve for the rectum. The independent association with larger percent volumes exposed to intermediate doses ( approximately 46 Gy) seen in both dose groups may indicate that a large surrounding region of intermediate dose may interfere with the ability to repair the effects of a central high dose region."