Hypofractionated Intensity Modulated Radiotherapy (70 Gy at 2.5 Gy Per Fraction) for Localized Prostate Cancer: Long-Term Outcome Results

S124

I. J. Radiation Oncology

● Biology ● Physics

Volume 63, Number 2, Supplement, 2005

Results: One hundred and seventy-four patients (58:116) were matched. The median follow-up time was 6 years from the time of surgery. After controlling for the prognostic factors by the matching, there was a significant improvement in long-term PSA control with early adjuvant RT vs. delayed salvage RT. The 5-year Kaplan-Meier freedom from PSA failure was 68% (95% confidence interval [CI]: 54% to 82%) after adjuvant RT as compared to 42% (95% CI: 32% to 52%) for those undergoing salvage RT at time of PSA failure (Log-Rank p⫽.0087). On multivariate analysis we found that salvage RT (Hazard Ratio⫽ 2.1, p⫽.0047), SVI, and Gleason score above 7 were independent predictors of increased biochemical failure (all p⬍0.01). Conclusions: Early postoperative adjuvant RT for pT3/4N0 prostate cancer significantly reduces the risk of long-term disease progression after radical prostatectomy as compared to delayed salvage RT. Its effect on overall survival awaits additional follow-up data.

205

A Multi-Institutional Phase I/II Trial of Dose-per-fraction Escalation for Localized Prostate Cancer

M.A. Ritter,1 R.J. Chappell,2 W.A. Tome,1 P.A. Kupelian3 Human Oncology, University of Wisconsin, Madison, WI, 2Biostatistics, University of Wisconsin, Madison, WI, 3Radiation Oncology, M.D. Anderson Cancer Center, Orlando, FL 1

Purpose/Objective: A lower indicated alpha/beta ratio for prostate cancer control than for rectal toxicity suggests that radiation hypofractionation (HFX) could increase the therapeutic ratio. We have undertaken a novel phase I/II clinical trial to assess the tolerability and efficacy of increasingly HFX’d regimens. The first level of this ongoing three-level, increasingly hypofractionated trial is complete. The trial design and initial results are presented. Materials/Methods: Three increasingly HFX’d levels were designed per LQ modeling to maintain approximately constant predicted late toxicity (assuming an alpha/beta of 3) relative to 76 Gy in 38 fractions. Novel aspects of the trial design include a fractions-per-week escalation (first 4, then 5) nested within each HFX level to limit possible acute and consequential rectal toxicities, as well as a prorated analysis of grade 2 rectal bleeding, the designated HFX escalation-limiting toxicity. The planned HFX levels I, II and III (and targeted accruals) are 64.7 Gy/ 22 fx of 2.94 Gy (50 pts), 58.08 Gy/ 16 fx of 3.63 Gy (50 pts) and 51.6 Gy/ 12 fx of 4.3 Gy (150 pts), respectively (table). These HFX schedules predict for tumor NTD doses (in 2 Gy fractions) equivalent to in excess of 80 Gy (see table), assuming a tumor alpha/beta ratio of 1.5. Tomotherapy or Linac-based IMRT with image guidance was used. Two institutions participated in completing level I accrual, with two additional academic institutions now joining to contribute to levels II and III accrual. Results: Level I accrual is complete with 50 patients. Toxicities were modest: The average IPSS score reached a maximum of 14/35 at 2 weeks post treatment, but then rapidly declined to about the pre-treatment baseline of 9. A 40% rate of acute grade 2 GU toxicity (based on alpha blockers use) during treatment declined to 12% by one year. Only minor grade I acute GI toxicities were seen during and shortly after treatment. Four vs. 5 treatments per week were equally well tolerated. Late rectal toxicities were also modest: The 50 patients (median follow-up 10 months) experienced a projected 9.6% rate of grade 2 GI toxicity (rectal bleeding) at two years, but no grade 3 toxicities. Interestingly, PSAs decreased with a median initial half-life of 1.3 months - about twice as rapidly as typical for standard fractionation. Conclusions: The first treatment level (22 fx of 2.94 Gy each) of a multi-institutional phase I/II prostate HFX trial has been completed with 50 patients accrued and with acceptable levels of acute and preliminary late toxicities were observed. Accrual to the next more HFXed level is underway with the ultimate goal of selecting a HFX regimen for phase III testing. Hypofractionation for prostate cancer is attractive for its potential therapeutic gain as well as its economic and logistic advantage.

206

Hypofractionated Intensity Modulated Radiotherapy (70 Gy at 2.5 Gy Per Fraction) for Localized Prostate Cancer: Long-Term Outcome Results

V.V. Thakkar,1 D. Khuntia,3 C.A. Reddy,1 E.A. Mahadevan,1 A. Klein,4 N. Chehade,5 P.A. Kupelian2 Department of Radiation Oncology, The Cleveland Clinic Foundation, Cleveland, OH, 2Department of Radiation Oncology, M.D. Anderson Cancer Center Orlando, Orlando, FL, 3Department of Human Oncology, University of Wisconsin, Madison, WI, 4Glickman Urologic Institute, The Cleveland Clinic, Cleveland, OH, 5Department of Urology, Kaiser Permanente, Cleveland, OH 1

Purpose/Objective: The aim of this study is to present our observations on relapse-free survival and toxicity on patients with long term follow-up after hypofractionated intensity modulated radiotherapy (HFRT) to a total of 70 Gy delivered at 2.5 Gy per fraction over 51⁄2 weeks. Materials/Methods: The study sample includes the first one hundred consecutive localized prostate cancer patients treated with HFRT at the Cleveland Clinic from 1998 to 1999. All patients had available pretreatment PSA levels (iPSA) and biopsy Gleason scores (GS). Treatment consisted of intensity-modulated radiotherapy using 5 static fields (anterior, 2 laterals, and 2 anterior obliques). Delivery was performed with a Dynamic Multi-Leaf Collimator. A total of 70.0 Gy was prescribed for all patients at 2.5 Gy per fraction to be delivered in 28 fractions over 5 1⁄2 weeks. The location of the prostate gland was verified and adjusted daily with the BAT™ transabdominal ultrasound system. Thirty-six patients had low-risk disease, 30 had intermediate risk disease, and 34 had high risk disease. Fifty-one patients received hormonal therapy for 6 months in combination with

Proceedings of the 47th Annual ASTRO Meeting

radiation. The median follow-up was 66 months (range: 3 to 75 months). Acute and late toxicities were measured using RTOG scores. Biochemical failure was the endpoint studied with both the ASTRO biochemical failure definition (A-bRFS) and the alternate “nadir ⫹ 2 ng/ml” definition (N-bRFS), resulting in two separate biochemical relapse free survival rates. Results: With median follow-up exceeding five years, the five-year biochemical relapse free survival rates are encouraging, with no significant differences between the five-year A-bRFS and five-year N-bRFS rates. The overall five-year A-bRFS rate was 85% (95%C.I.: 78 –93%), whereas the five-year N-bRFS rate was 88% (95%C.I.: 82–95%). For patients with low, intermediate and high risk disease, the 5-year A-bRFS rates were 97%, 88% and 70%. The five-year N-bRFS rates for patients with low, intermediate and high risk disease were 97%, 93% and 75%. The RTOG acute rectal toxicity scores were: 0 in 20 patients, 1 in 61 patients, and 2 in 19 patients. The RTOG acute urinary toxicity scores were: 0 in nine patients, 1 in 76 patients, and 2 in 15 patients. The RTOG late rectal toxicity scores were: 0 in 71 patients, 1 in 19 patients, 2 in seven patients, and 3 in three patients. The actuarial late RTOG grade 3 rectal toxicity rate at five years was 3%. Importantly, a number of the toxicities observed either resolved spontaneously or were corrected. At last follow-up, the combined RTOG late toxicity scores 2 and 3 at five years was only 5%, i.e. only 5% of patients were actually experiencing grade 2–3 rectal toxicity, often intermittent rectal bleeding. The RTOG late urinary toxicity scores were: 0 in 75 patients, 1 in 13 patients, 2 in 11 patients, and 3 in one patient. The actuarial late RTOG grade 3 urinary toxicity rate at five years was 1%. Conclusions: With a median follow of 66 months, long-term results after high-dose hypofractionation are excellent. Long term biochemical relapse-free survival rates are particularly encouraging at five years after treatment. Long term urinary and rectal toxicity has been limited. High-dose hypofractionation is an alternative method of dose escalation in the treatment of localized prostate cancer, and this schedule significantly increases convenience to patients due to the decrease in overall treatment time.

207

Patient-Assessed Late Toxicity Following High-Dose Image-Guided Radiation Therapy for Prostate Cancer and Correlation with Dose-Volume Histograms

M. Skala,1 C. Catton,1 L. Dawson,1 L. Divanbeigi,2 A. Bayley,1 R. Bristow,1 J. Crook,1 M. Gospodarowicz,1 M. McLean,1 M. Milosevic,1 T. Rosewall,2 P. Warde1 1 Radiation Oncology, Princess Margaret Hospital, Toronto, ON, Canada, 2Radiation Therapy, Princess Margaret Hospital, Toronto, ON, Canada Purpose/Objective: While dose escalation has been shown to improve disease-free survival in prostate cancer, it is also associated with a greater incidence of late rectal toxicity. Numerous studies of dose-volume histograms (DVHs) have shown that rectal toxicity is positively correlated with the percentage of rectal wall exposed to high radiation doses. We report the incidence of patient-assessed late toxicity following high-dose image-guided 3DCRT and IMRT in a large cohort of men with localised prostate cancer. Late gastro-intestinal (GI) and genito-urinary (GU) toxicity are analysed using conventional dosimetric parameters as well as principal component analysis. The latter is a novel approach reported by Dawson et al that efficiently describes the variance in cumulative DVH morphology. Materials/Methods: A previously published late toxicity postal questionnaire was sent to 754 men who were treated at the Princess Margaret Hospital (PMH) for localised prostate cancer between 1997 and 2003. All patients had 3 prostate fiducial markers inserted before treatment planning, to allow daily image guidance. The clinical target volume encompassed the prostate gland only, and received 75.6 Gy or 79.8 Gy using 3DCRT or IMRT. Patient reported toxicity was graded using the modified RTOG-LENT scoring system. The toxicity scores were dichotomized as ⬍ grade 2 and ⱖgrade 2, and using the non-parametric Mann-Whitney test, correlated with the following dosimetric parameters: volume of rectal and bladder wall within Planning Treatment Volume, mean and maximum rectal and bladder wall dose, volume of rectal and bladder wall receiving ⱖ50Gy, ⱖ60Gy, ⱖ70Gy, and with the principal components chosen as being descriptive of the variability of the datasets. Results: 416 (55%) men responded to the questionnaire. At a median follow-up of 3.5 years, the incidence of RTOG Grade 0 late GI toxicity was 75%, Grade 1–23%, Grade 2–1.2% and Grade 3–1.0%. Four patients experienced Grade 3 GI toxicity. Two reported prolonged use of rectal steroid, one reported persistent use of incontinence pads, and one underwent numerous coagulation procedures. The incidence of RTOG Grade 0 late GU toxicity was 71%, Grade 1–23%, Grade 2– 4.3% and Grade 3–1.0%. Four patients experienced Grade 3 GU toxicity. Three reported persistent use of incontinence pads, and one experienced nocturia more frequently than every hour. Patient-reported pre-treatment potency rate was 73%. Following treatment, 68% of previously potent men were able to achieve erections sufficient for intercourse, and 45% reported no change in potency. Use of PDE-5 inhibitors was reported by 18% of men, and 83% found these to be effective. To date, we have retrieved the electronic DVHs for 51 of these men. Neither dosimetric parameter analysis, nor PCA showed a significant correlation with toxicity. Conclusions: The incidence of Grade ⱖ2 late RTOG GI and GU toxicity following high-dose radiotherapy at PMH is ⬍5%. Although patient-assessed toxicity is generally worse than physician-assessed toxicity, the incidence in our study is lower than anticipated from other published data. We attribute this to the use of conformal techniques and image-guidance. With a low number of adverse events, our preliminary analysis is not sufficiently powered to detect a correlation between toxicity and dosimetric parameters or primary components. We anticipate that there will be sufficient events to demonstrate a correlation between late toxicity and irradiated volumes of rectal and bladder wall and the DVH principal components in the final analysis.

208

Localized Volume Effects for Late Rectal and Anal Toxicity After Radiotherapy for Prostate Cancer

S. Peeters,1 J. Lebesque,1 W. Heemsbergen,1 W. van Putten,2 A. Slot,3 M. Dielwart,4 P. Koper2 Netherlands Cancer Institute, Amsterdam, Netherlands, 2Erasmus MC, Rotterdam, Netherlands, 3Radiotherapeutic Institute Friesland, Leeuwarden, Netherlands, 4Zeeuws Radiotherapeutic Institute, Vlissingen, Netherlands 1

Purpose/Objective: To identify dosimetric variables derived from anorectal or anal wall dose distributions that correlate with various late GI toxicity endpoints in patients treated with 3D-conformal RT for localized prostate cancer.

S125