Patterns of Lymph Node Failure After Dose-Escalated Radiation Therapy in Patients Who Did Not Undergo Pelvic Lymph Node Irradiation: Implications for Extended Pelvic Lymph Node Coverage

Volume 96  Number 2S  Supplement 2016

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Author Disclosure: P. Alexidis: None. J.P. Christodouleas: None. J.E. Bekelman: None. N. Vapiwala: None. P.E. Gabriel: None.

2581 Hypofractionated Dose Painting Intensity Modulated Radiation Therapy for Intermediate- to High-Risk Localized Prostate Cancer: Treatment With 20 Fractions J. Chan, T. Rowntree, J.N. Brunt, L. Howard, and I. Syndikus; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, United Kingdom Purpose/Objective(s): The CHHiP trial has shown non-inferiority of 60Gy/20# schedule compared to conventional 74Gy/37# for biochemical control at 5 years. Prostate dose-painting (boosting intra-prostatic tumor volumes, standard dose to prostate outside boost volume) may improve biochemical relapse-free survival similar to whole organ dose-escalation, whilst avoiding increased associated toxicity. We present dose painting radiation therapy results for a phase II trial: intermediate to high risk patients treated with 60Gy/20# and concurrent 68Gy boost to intra-prostatic lesions. Materials/Methods: Patients had a multi-parametric MRI and 18F choline PET/CT prior to androgen deprivation (ADT), and planning MRI and CT following 2 months’ ADT. Registration used fiducial markers. Intra-prostatic boost volumes were outlined by combining visually identified lesions on MRI and PET. Rotational IMRT planning was performed using Pinnacle software. Patients with unexpected regional lymph node PET uptake also received pelvic radiation therapy with boost. Toxicity evaluation was performed with CTCv.4.0 and RTOG scale. Endpoint was acute toxicity at 18 weeks. Results: Fifty-three patients were planned and treated, 5 with concurrent pelvic radiation therapy. Median age and PSA was 67 years (range 50-77) and 10.0ng/ml (3.9-39.4), 13 patients had intermediate and 40 had high risk disease. For all patients, median prostate boost volume was 13.5ml (range 8.1-33.1). Median prostate dose excluding boost was 61.0Gy. Median intra-prostatic boost dose was 68.1Gy. In pelvic radiation therapy group, lymph node dose of 45Gy with boost to 50Gy was achievable, as were normal tissue dose volume constraints (bladder, urethra, rectum and bowel) (Table). Grade 2 urinary toxicity at baseline was 12%, increasing to 26% during radiation therapy and 1 patient had grade 3 toxicity (RTOG). At week 18, the results were back to baseline. Bowel toxicity was modest: 12% developed grade 1 and 5% grade 2 during radiation therapy, with 5% with grade 1 and 2 at 18 weeks. Conclusion: Prostate radiation therapy with hypofractionated dose painting schedule of 60Gy/20# with 68Gy boost to intra-prostatic lesions was well tolerated in this cohort study. Abstract 2581; Table 1.

Prostate without boost (Gy)

Prostate boost volume (Gy)

LN without boost (Gy) LN boost volume (Gy) Rectum (%)

Bladder (%)

D2% D50% D98% D2% D50% D98% D50% Min. dose D50% Min. dose V48.6 Max. dose Mean dose V48.6 Max. dose Mean dose

Dose painting to prostate only (n Z 48)

Dose painting to prostate and LN (n Z 5)

Median (Range)

Median (Range)

66.4 61.0 58.1 70.1 68.1 60.9

(64.1-69.0) (60.4-61.7) (57.2-59.0) (69.0-71.0) (66.2-68.9) (59.2-64.2)

15.0 62.3 21.6 11.2 63.4 18.2

(9.1-33.3) (58.2-66.4) (15.0-32.3) (3.1-31.9) (60.7-67.1) (7.1-35.9)

66.2 61.0 58.0 70.3 67.2 62.0 45.2 35.7 51.0 48.6 17.8 62.8 29.0 19.8 64.1 39.6

(64.7-67.6) (60.9-61.2) (57.1-58.3) (69.2-71.0) (66.8-68.5) (59.5-64.6) (45.1-45.7) (35.5-40.0) (50.1-51.4) (46.4-49.0) (6.0-18.3) (61.6-64.6) (23.1-33.9) (9.3-26.9) (62.5-65.4) (32.5-42.2)

Author Disclosure: J. Chan: None. T. Rowntree: None. J.N. Brunt: None. L. Howard: None. I. Syndikus: None.

2582 Natural History of Progression After Biochemical Failure Following Postoperative Radiation Therapy in Prostate Cancer V. Tumati,1 D.E. Spratt,2 W.C. Jackson,2 F.Y. Feng,2 C. Roehrborn,1 Y. Lotan,1 D.A. Pistenmaa,1 A.M. Laine,1 M.R. Folkert,1 R. Hannan,1 and N.B. Desai1; 1University of Texas Southwestern Medical Center, Dallas, TX, 2University of Michigan, Ann Arbor, MI Purpose/Objective(s): Post-operative radiation therapy (PORT) is an effective treatment for appropriately selected prostate cancer patients after radical prostatectomy (RP). The natural history of disease after biochemical recurrence (BCR) following PORT has not been well described. This study examined the clinical course of patients who underwent PORT and experienced a BCR. Materials/Methods: A retrospective multi-institutional study was performed on 608 consecutive men who received PORT following RP between 1986 and 2013. BCR was defined as a rise in PSA of 0.2 ng/mL or greater above the PSA nadir followed by a sequentially equal or higher PSA. Two hundred ninety-seven men had a BCR and formed the study cohort. Actuarial estimates of freedom from BCR, freedom from castration resistant prostate cancer (CRPC), prostate cancer specific survival (PCSS), overall survival (OS), local, regional, and distant recurrence (DM) were determined using the Kaplan-Meier method. Castrate resistance was defined as 2 episodes of rising PSA with testosterone <50 ng/ml. Statistical analysis was performed using log-rank and Cox proportional hazard testing. Results: The median follow-up from time of BCR was 72 months. Actuarial 72 months, local recurrence, regional recurrence, DM, CRPC PCSS, and OS were 5%, 8%, 40%, 29%, 81%, and 75%, respectively. Median time to DM and to OS after BCR were 107 and 154 months, respectively. For men who developed DM after BCR, subsequent median OS and PCSS were 59 and 67 months, respectively. On univariate analysis, pre-PORT PSA > 0.4 (P Z .03), T stage > T2c (P Z .019), N+ (P Z 0.05), and whole pelvic RT (P Z 0.01) were associated with worse OS. On multivariate analysis only pre-PORT PSA >0.4 remained significantly associated with worse OS (HR 1.7 P Z 0.04). A total of 203 men received ADT after BCR, of whom 69 received immediate ADT within 3 months of BCR. Of the men who developed CRPC, 45 went on to receive 2nd generation ADT, 29 received chemotherapy, 2 received sipuleucel-T, and 7 received radium-223. Conclusion: Men who suffer BCR after PORT have a long survival, with high rates of PCSS. However, 6-years after BCR 40% of patients will have developed metastatic disease, despite the frequent use of ADT, and nearly 20% will have died from prostate cancer. Given these high rates of distant failure, further systemic intensification of therapy is warranted with PORT in men with prostate cancer, particularly in those with baseline adverse features such as pre-PORT PSA >0.4. Author Disclosure: V. Tumati: None. D.E. Spratt: None. W.C. Jackson: None. F.Y. Feng: None. C. Roehrborn: None. Y. Lotan: None. D.A. Pistenmaa: None. A.M. Laine: None. M.R. Folkert: None. R. Hannan: None. N.B. Desai: None.

2583 Patterns of Lymph Node Failure After Dose-Escalated Radiation Therapy in Patients Who Did Not Undergo Pelvic Lymph Node Irradiation: Implications for Extended Pelvic Lymph Node Coverage D.E. Spratt,1,2 H.A. Vargas,3 Z.S. Zumsteg,4 J. Golia Pernicka,3 J. Osborne,3 S.M. McBride,2 M.A. Kollmeier,2 X. Pei,2 and M.J. Zelefsky2; 1University of Michigan, Ann Arbor, MI, 2Memorial Sloan Kettering Cancer Center, New York, NY, 3Memorial Sloan Kettering, New York, NY, 4Cedars-Sinai Medical Center, Los Angeles, CA Purpose/Objective(s): Clinical trials evaluating the benefit of pelvic radiation therapy in the radiotherapeutic management of patients with higher risk prostate cancer have limited the superior field border to the S1/S2 or L5/S1 interspace. However, imaging and surgical series have demonstrated a high frequency of prostatic lymph node (LN) drainage beyond these

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landmarks. We aimed to determine the patterns of radiographically-defined abdomino-pelvic LN failures and their potential implications for pelvic radiation therapy field design in men who received dose escalated radiation therapy without pelvic LN irradiation. Materials/Methods: From 1992-2008, 2,694 patients with localized prostate cancer were treated with prostate/seminal vesicle only radiation therapy without pelvic LN treatment. One hundred-fifty six patients had their first failure within the abdominopelvic LNs, of which 60 had isolated failures within the pelvic LNs. A radiologist reviewed all imaging and mapped each LN failure to a template consisting of 34 abdomino-pelvic LN stations. Univariate and multivariate Cox regression analyses were performed to identify predictors of the likelihood of failure superior to the L5/S1 interspace. Results: The median follow-up was 8.9 years. Of patients who recurred only in the pelvic LNs (n Z 60), the common iliac LN station was involved in 55% (n Z 33), including 10% (n Z 6) having isolated common iliac LN failures. Using a pelvic radiation field superior border of L5/ S1 would fully cover only 42% of these patients’ first recurrences whereas extending the field to L4/L5 would increase coverage to 93% of recurrences. Presence of T3/T4 disease and omission of androgen deprivation therapy both independently conferred an approximate 5-fold increase in the likelihood of having LN failure between L4/5 and L5/S1 in addition to standard pelvic field failures. Conclusion: Pelvic LN failures occur frequently superior to the commonly used L5/S1 landmark for pelvic radiation therapy coverage. The current RTOG 0924 trial is evaluating the benefit of pelvic radiation therapy with extended superior coverage to L4/5 when possible, which based on our data should significantly improve coverage of potential sites of failure. Author Disclosure: D.E. Spratt: Research Grant; Prostate Cancer Foundation. H.A. Vargas: None. Z.S. Zumsteg: None. J. Golia Pernicka: None. J. Osborne: None. S.M. McBride: None. M.A. Kollmeier: None. X. Pei: None. M.J. Zelefsky: None.

ratio [HR]: 1.04, 95% confidence interval [CI]: 1.03-1.06) and non-academic facility (HR: 1.34, 95% CI: 1.03-1.74) were associated with worsened OS. cADT (HR: 0.82, 95% CI: 0.65-1.03) and RT dose 75.6 Gy (HR: 1.01, 95% CI: 0.78-1.31) were not associated with differences in OS. On multivariate analysis when controlling for Charlson Comorbidity score, radiation dose (<75.6 vs 75.6 Gy), PSA and clinical T-stage, independent variables associated with improved OS were cADT (HR: 0.67, 95% CI: 0.51-0.88), whereas age 65 (HR: 1.73, 95% CI: 1.16-2.57), nonacademic facility type (HR: 1.47, 95% CI: 1.09-2.00) and Gleason 4+3 (vs. 3+4) (HR: 1.36, 95% CI: 1.04-1.78) disease were associated with worsened OS. There was a positive interaction between increased age and cADT use, as well as treatment at a non-academic facility and cADT use, on improved OS. On subset analysis of patients receiving dose-escalated RT (75.6 Gy), cADT was borderline significant (HR: 0.68, 95% CI: 0.46-1.01, P Z 0.058) on multivariate analyses. Conclusion: For men with unfavorable intermediate risk PCa, treatment with cADT was independently associated with improved OS. These results support aggressive treatment with cADT in the setting of dose-escalated RT. The interaction of increased age as well as non-academic facility with the association between cADT and improved OS indicates that there may be some selection bias in selecting healthier patients for cADT. However, longer follow up, analysis of datasets with more specific clinical outcomes, and continued study is needed to establish the true benefit of contemporary RT and cADT in this specific risk group. Author Disclosure: S.B. Johnson: None. N.H. Lester-Coll: Honoraria; Elekta. J.M. Stahl: None. S.K. Nath: None. J.B. Yu: Research Grant; 21st Century Oncology.

2584 Withdrawn

2585 Impact of Concurrent Androgen-Deprivation Therapy and Radiation Therapy Versus Radiation Therapy Alone on Overall Survival for Men With Unfavorable Intermediate-Risk Prostate Cancer S.B. Johnson,1 N.H. Lester-Coll,2 J.M. Stahl,2 S.K. Nath,1 and J.B. Yu3; 1 Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, 2Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, 3Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale School of Medicine, New Haven, CT Purpose/Objective(s): There is limited evidence related to the overall survival (OS) benefit of dose-escalated radiation therapy (RT) and concurrent androgen deprivation therapy (cADT) in men with clinically localized prostate cancer (PCa). Here we examine the association between OS and definitive RT with or without cADT in men with unfavorable intermediate risk PCa. Materials/Methods: We conducted a retrospective analysis of men with unfavorable intermediate risk PCa (Gleason 4+3 or 2 intermediate risk factors [prostate specific antigen (PSA) 10 to <20 ng/ml, Gleason 3+4, T2b-T2c]) treated with external beam RT (68.4-86.4 Gray [Gy]) with or without cADT, defined as administration within 90 days of RT from 20042006, using the National Cancer Database. Univariate and multivariate survival analyses with interaction variables were completed using Coxproportional hazards models. Subset analysis of dose-escalated RT was completed using log rank, Kaplan-Meier methods, and Cox-proportional hazards model. Results: Among 786 patients with mean follow up of 77.6 months (standard deviation, 32.1), 307 (39.1%) patients were treated with RT alone and 479 (60.9%) patients with RT+cADT. On univariate analysis, age (hazard

2586 Identifying a Subgroup of High-Risk Prostate Cancer Patients With Worse Clinical Outcomes: Should There Be a “Very High-Risk” Group? S. Choi,1 L.B. Levy,1 K.K. Lee,1 Q.N. Nguyen,2 A.K. Lee,3 S.E. McGuire,1 R. Kudchadker,1 W. Du,1 K.E. Hoffman,1 U. Mahmood,1 S.J. Frank,1 and D.A. Kuban1; 1The University of Texas MD Anderson Cancer Center, Division of Radiation Oncology, Houston, TX, 2Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 3Texas Center for Proton Therapy, Irving, TX Purpose/Objective(s): Standard recommendation for treatment of highrisk prostate cancer patients currently includes external beam radiation therapy and long-term hormone ablation therapy with a GnRH agonist, which has a greater than 20% biochemical relapse rate. However, high-risk prostate cancer encompasses a large spectrum of disease with variable response to standard treatment. This analysis attempts to identify a group of high-risk patients with poorer outcomes with standard treatment who may benefit from more aggressive therapy. Materials/Methods: 741 patients with high-risk prostate cancer (stage T3a, Gleason score 8, or prostate specific antigen (PSA) 20 ng/ml) treated between 1987 and 2004 at a single institution were included in this study. Among these patients, 108 patients who had both stage T3a and Gleason score 9 were identified. Clinical outcome of this cohort was compared to the remaining high-risk patients using a log-rank test. Biochemical relapse was defined as PSA above nadir + 2 ng/mL. All patients were treated to the prostate and seminal vesicles to a median radiation dose of 70 Gy (range 60-79.2 Gy) given at 1.8 to 2.0 Gy per fraction. Pelvic lymph nodes were not treated. All patients received androgen deprivation therapy (ADT). ADT was started 2 to 3 months before radiation therapy and continued for a median of 2.9 years (range 218 years). Results: Median follow-up was 8.3 years (range 0.13-20 years). Patients with both stage T3a and Gleason score 9 prostate cancer had decreased 10-year salvage treatment free survival (56% vs 78%, P<0.0001), distant metastases-free survival (70% vs 90%, P Z 0.009), and overall survival (52% vs 68%, P Z 0.0424) than high-risk patients who did not have both of these risk factors. Patients with both risk factors also had decreased 10-year prostate cancer specific survival and nodal relapse free survival; however