# Radiation Oncology/RTOG Trials/9406

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
RTOG 94-06 (PROSTATE)
* Title: A Phase I/II Dose Escalation Study Using 3D-CRT for Adenocarcinoma of the Prostate
* Objectives:
** (1) To establish the maximum tolerated dose (MTD) of radiation that can be delivered to the prostate gland and immediate surrounding tissues in patients with carcinoma of the prostate using three dimensional conformal radiation therapy (3D-CRT).
** (2) To quantify the normal tissue toxicity rate (normal tissue complication probability [NTCP]) for rectum and bladder using 3D-CRT.
** (3) To evaluate local control by clinical, pathologic, and PSA (stable in normal range) determinations.
* Protocol: Dose escalation [Gy]: Level I =68.4 (1.8 Gy/fx) -> Level II = 73.8 (1.8 Gy/fx) -> Level III = 79.2 (1.8 Gy/fx) -> Level IV = 74.0 (2.0 Gy/fx) -> Level V = 78.0 (2.0 Gy/fx)
* Eligibility: (T1b-T2b and GS >=6 and PSA >4) or (T3), N0M0
** Grouping:
*** Group 1: Clinical stages T1b-c or T2a-b with PSA + ([Gleason -6] x 10) is <= 15.
*** Group 2: Clinical stages T1b-c or T2a-b with PSA + ([Gleason -6]x10)>15. Any clinical T2c with PSA < 70. Must be lymph node negative.
*** Group 3: Clinical stage T3 with PSA < 70. Must be lymph node negative.
* Treatment Group:
** Group 1: GTV=Prostate; CTV = prostate (no margin); PTV = CTV + 0.5-1.0 cm"
** Group 2: GTV=Prostate; CTV1 = Prostate + BSV(=Bilateral seminal vesicles); CTV2 = Prostate; PTV1 = CTV + 0.5-1.0 cm; PTV2 = CTV2 + 0.5-1.0 cm
** Group 3: GTV=Prostate+BSV; CTV = Prostate + BSV (no margin); PTV = CTV + 0.5-1.0 cm
* Enroll Target: Dose tolerance dependent
* Activated: May 2, 1994
* Closed: October 31, 2000
* Conclusion:
** Long-Term Toxicity; 2010 PMID 19577865 -- "Long-Term Toxicity Following 3D Conformal Radiation Therapy for Prostate Cancer from the RTOG 9406 Phase I/II Dose Escalation Study." (Michalski JM, Int J Radiat Oncol Biol Phys. 2010 Jan 1;76(1):14-22.) - Tolerance excellent; more late toxicity with 2 Gy/fx than with 1.8 Gy/fx
* Publications:
** PMID 22633552 -- Clinical Outcome of Patients Treated With 3D Conformal Radiation Therapy (3D-CRT) for Prostate Cancer on RTOG 9406. (Michalski J, Int J Radiat Oncol Biol Phys. 2012) Conclusion "Dose-escalated 3D-CRT yields favorable outcomes for localized prostate cancer. This multi-institutional experience allows comparison to other experiences with modern radiation therapy."
** PMID 15936549 -- Toxicity after three-dimensional radiotherapy for prostate cancer on RTOG 9406 dose Level V. (Michalski JM, Int J Radiat Oncol Biol Phys. 2005) Conclusion: "Tolerance to three-dimensional conformal radiotherapy with 78 Gy in 2-Gy fractions remains better than expected compared with historical controls. The magnitude of any effect from fraction size and treatment volume requires additional follow-up."
** PMID 14967428 -- Toxicity after three-dimensional radiotherapy for prostate cancer with RTOG 9406 dose level IV. (Michalski JM, Int J Radiat Oncol Biol Phys. 2004). Conclusion: Tolerance to three-dimensional conformal radiotherapy with 74 Gy in 2-Gy fractions remains better than expected compared with historical controls. The magnitude of any effect from fraction size requires additional follow-up.
** ASCO Abstract -- Clinical outcome of patients treated with 3D conformal radiation therapy 3D-CRT for prostate cancer on RTOG 9406 (Michalski JM, ASCO 2005). Conclusion: The biochemical disease free survival appears comparable to other series using 3D CRT for localized prostate cancer. A randomized RTOG trial comparing 70.2 Gy vs 79.2 Gy for intermediate risk patients is ongoing.
** ASTRO Abstract -- Clinical Outcome of Patients Treated with 3D Conformal Radiation Therapy 3D-CRT for Prostate Cancer on RTOG 9406 (Michalski, ASTRO 2004). Conclusion: Previous reports from RTOG 9406 have demonstrated safety of dose escalation using 3D CRT for treatment to radiation doses as high as 79.2Gy and 1.8Gy per day or 78Gy and 2.0Gy per day fractions. The clinical disease-free survival (without 9406 PSA definition) appears comparable to other series using 3D CRT for localized prostate cancer. Analysis using ASTRO and other more sensitive and specific definitions of radiation therapy outcome will be presented. Analyses of outcome by prognostic factors including T-stage, initial PSA, Gleason score, and the use of neoadjuvant hormone therapy is planned.
** PMID 15590164 -- Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: findings from a prospective, multi-institutional, phase I/II dose-escalation study. (Roach M, IJROBP 2004). Conclusion: Dose to the bulb of the penis seems to be associated with the risk of radiation-induced impotence.
** PMID 12694838 -- Preliminary evaluation of low-grade toxicity with conformal radiation therapy for prostate cancer on RTOG 9406 dose levels I and II. (Michalski JM, IJRBOP 2003). Conclusion: Morbidity of 3D-CRT in the treatment of prostate cancer is low. It is important to continue to closely examine late effects in patients treated in RTOG 9406. The primary objective of dose escalation without an increase rate of >/= Grade 3 sequelae has been achieved. However, the reduction in Grade 3 complications may have resulted in a higher incidence of Grade 1 or 2 late effects. Because Grade 2 late effects may have a significant impact on a patient's quality of life, it is important to reduce these complications as much as possible. Clinical trials should use quality-of-life measures to determine that trade-offs between severity and rates of toxicity are acceptable to patients.
** PMID 14529764 -- RTOG 94-06: is the addition of neoadjuvant hormonal therapy to dose-escalated 3D conformal radiation therapy for prostate cancer associated with treatment toxicity? (Valicenti RK, IJROBP 2003). Conclusion: Neoadjuvant HT did not show an independent effect on the risk of side effects after 3D-CRT in patients treated on RTOG 94-06. However, this combined modality therapy significantly increased the risk of acute GU effects compared to 3D-CRT alone in men with poor baseline urinary function.
** ASTRO Abstract -- Toxicity Following 3D Radiation Therapy for Prostate Cancer on RTOG 9406 Dose Level V (Michalski J, ASTRO Abstract 46, 2003). Conclusion: The rate of grade 3+ toxicity from 3DCRT with 78 Gy in 2.0 Gy fractions remains better than expected compared to historical controls. However, low grade late toxicity is significantly higher in dose level V than dose level III. These differences may be dose and/or volume related.
** PMID 12419429 -- Interim report of toxicity from 3D conformal radiation therapy (3D-CRT) for prostate cancer on 3DOG/RTOG 9406, level III (79.2 Gy). (Ryu JK, IJRBOP 2002). Conclusion: Based on excellent tolerance of 3D-CRT for stages T1 and T2 prostate cancer, further biological dose escalation has been pursued to Levels IV and V, 74 Gy and 78 Gy, respectively, at 2 Gy per day, in an attempt to reduce the total treatment duration. This trial has closed. A Phase III comparative RTOG trial is being developed to determine whether high-dose 3D-CRT improves efficacy.
** PMID 11917289 -- Trade-off to low-grade toxicity with conformal radiation therapy for prostate cancer on Radiation Therapy Oncology Group 9406. (Michalski JM, Semin Radiat Oncol 2002). Conclusion:The primary objective of dose escalation without an increase rate of > or = grade 3 complications has been achieved. However, the reduction in grade 3 complications may have resulted in a higher incidence of grade 2 late effects. Because grade 2 late effects may have a significant impact on a patient's quality of life, it is important to reduce these complications as much as possible.
** ASTRO Abstract -- Toxicity Following 3D Radiation Therapy For Prostate Cancer On RTOG 94-06 Dose Level IV. (Michalski JM, ASTRO 2002; Int J Radiat Oncol Biol Phys [54] (2):107, 2002.
*** Results: At dose level IV, grade 3 acute effects in 1% (Group 1) and 3% (Group 2). No grade 4 or 5. Late toxicity is low compared to historical controls: grade 3 bladder (1 in group 1, 4 in group 2), grade 3 bowel (1 in group 2), no grade 4 or 5. Late grade 2 toxicities of any type in 22% (group 1) and 15% (group 2). No difference in rate of acute/late toxicity for 73.8 Gy/1.8 vs 74 Gy/2.0. Trend toward more grade 3 or higher toxicity with 2 Gy fractions vs 1.8 Gy p=0.09).
*** Conclusion: Tolerance to 3DCRT with 74 Gy in 2Gy fractions remains better than expected compared to historical controls. The magnitude of any effect from fraction size requires additional follow-up.
** ASTRO Abstract -- The Effect On Toxicity Of Induction Hormonal Therapy In Prostate Cancer Patients Receiving Dose Escalated 3D Conformal Radiation Therapy On RTOG 94-06. (Valicenti R, ASTRO 2002; Int J Radiat Oncol Biol Phys [54] (2):133-134, 2002.) Conclusion: Induction HT did not have an independent effect on the risk of side effects after 3D CRT. However, induction HT combined with 3D CRT significantly increased the risk of acute GU effects compared to 3D CRT alone in men with poor baseline urinary function. In patients receiving 3D CRT, no more than 30% of bladder volume should exceed the prescribed reference dose.
** ASCO Abstract -- Interim Report of Toxicity from 3D Conformal Radiation Therapy (3DCRT) for Prostate Cancer on 3DOG/RTOG 9406, Level III (79.2 GY). (Ryu JK, ASCO 2001). Conclusion: The observed rate of grade 3+ late effects for G1 (2 cases) is significantly lower (p=0.0012) than the 10.5 cases that were expected from RTOG 7506 and 7706. The observed rate for G2 (1 case) is significantly lower (p=0.0038) than the 8.4 cases expected. Based on the excellent tolerance of 3DCRT for stage T1,2 prostate cancer, further dose escalation has been pursued to levels IV and V, 74 Gy and 78 Gy respectively, at 2 Gy/day, in an attempt to reduce the total treatment duration.
** PMID 10661346 -- Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406. (Michalski JM, IJRBOP 2000). Conclusion: Tolerance to high-dose 3D CRT has been better than expected in this dose escalation trial for Stage T1,2 prostate cancer compared to low-dose RTOG historical experience.
** Michalski JM, Winter K, Purdy JA, et al.: Update of toxicity following 3D radiation therapy for prostate cancer on RTOG 9406. Int J Radiat Oncol Biol Phys 48(3 suppl): A-233, 228, 2000.
** Roach M, Winter K, Michalski J, et al.: Mean dose of radiation to the bulb of penis correlates with risk of impotence at 24 months: preliminary analysis of Radiation Therapy Oncology Group (RTOG) phase I/II dose escalation trial 94-06. Int J Radiat Oncol Biol Phys 48(3 suppl): A-2104, 316, 2000