2005 ASTRO Booklet [PDF]

Reference	Study #(s)
Langer, C., Swann, S., Curran Jr, W., Movsas, B., Werner-Wasik, M., Komaki, R., Lee, J.S. and Choy, H.: Reassessing Prognostic Factors in the Era of Combined Modality Therapy for Locally Advanced NSCLC: A Retrospective Analysis of RTOG 9410 and 9801. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys,[63] (Suppl. 1), pg. S39-S40, Abs. #65, 2005.	9410, 9801 (acc as oral pres)
Komaki, R., Swann, S., Curran Jr, W., Robert, F., Werner-Wasik, M., Lee, C., Jafar, S., Share, R., Choy, H. and Blumenschein, G.: A Phase II Study of Cetuximab (C225) in Combination with Chemoradiation (CRT) in Patients (PTS) with Stage IIIA/B Non-Small Cell Lung Cancer (NSCLC): An Interim Overall Toxicity Report of the RTOG 0324 Trial. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S44, Abs. #72, 2005.	0324 (acc as oral pres)
Pajak, T., Trotti, A., Gwede, C., Paulus, R., Cooper, J., Ridge, J.A., Fu, K. and Ang, K.K.: The TAME Risk Classification System: Acute Toxicity Burden and IPD Analysis of RTOG 90-03. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S131, Abs. #217, 2005.	9003 (acc as oral pres)
Horwitz, E., Harris, J., Langer, C., Nicolaou, N., Kies, M., Curran Jr, W., Wong, S. and Ang, K.K.: Phase II Study of Paclitaxel and Cisplatin in Combination with Split Course Concomitant Hyperfractionated Re-Irradiation in Patients with Recurrent Squamous Cell Cancer of the Head and Neck: Results of RTOG 99-11. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S72-S73, Abs. #119, 2005.	9911 (acc as oral pres)
Gaffney, D., Winter, K., Dicker, A., Miller, B., Jhingran, A., Ryu, J., Avizonis, V.N., Fromm, M. and Greven, K.: A Phase I-II Study of COX-2 Inhibitor, Celebrex (Celecoxib) and Chemoradiation in Patients With Locally Advanced Cervical Cancer: Primary Endpoint Analysis of RTOG 0128. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S93-S94, Abs. #155, 2005.	0128 (acc as oral pres)
Small Jr, W., Winter, K., Levenback, C., Iyer, R., Gaffney, D., Asbell, S., Erickson, B. and Greven, K.: Extended Field Irradiation and Intracavitary Brachytherapy Combined with Cisplatin Chemotherapy for Cervical Cancer with Positive Para-aortic or High Common Iliac Lymph Nodes: Results of Arm 1 of RTOG 0116. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S94, Abs. #156, 2005.	0116 (acc as oral pres)
Konski, A., DeSilvio, M., Hartsell, W., Watkins-Bruner, D., Scarantinio, C., Coyne, J. and Janjan, N.: Continuing Evidence for Poorer Treatment Outcomes for Single Male Patients: Re-treatment Data from RTOG 97-14. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, pg. Abs. SUBMITTED.	9714 (acc as poster disc)
Garden, A., Harris, J., Jones, C., Trotti, A., Carrascosa, L., Cheng, J., Spencer, S., Weber, R. and Ang, K.K.: Concomitant Boost Radiation and Concurrent Cisplatin for Advanced Head and Neck Carcinomas: Update of a Phase II Trial of the RTOG (99-14). Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S71-S72, Abs. #117, 2005.	9914 (acc as oral pres)
Zhang, M., Ho, A., Hammond, E., Roach III, M., Sause, W., Pilepich, M., Shipley, W., Sandler, H., Pollack, A. and Chakravarti, A.: The Prognostic Value of Surviving in Locally Advanced Prostate Cancer: A Study Based on RTOG 8610. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S18, Abs. #31, 2005.	8610 (acc as oral pres)
Zhai, G., Ho, A., Hammond, E., Fontanesi, J., Rotman, M., Pilepich, M., Shipley, W., Sandler, H., Pollack, A., Zhang, H. and Chakravarti, A.: Phospho-AKT Expression and Prognosis of Locally Advanced Prostate Cancer: A Study Based on RTOG 8610. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S319, Abs. #2152, 2005.	8610 (acc as poster pres)
Trotti, A., Fu, K., Pajak, T., Jones, C.U., Spencer, S.A., Phillips, T.L., Garden, A.S., Ridge, J.A., Cooper, J.S. and Ang, K.: Long Term Outcomes of RTOG 90-03: A Comparison of Hyperfractionation and Two Variants of Accelerated Fractionation to Standard Fractionation Radiotherapy for Head and Neck Squamous Cell Carcinoma. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO,Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S70-S71, Abs. #116, 2005.	9003 (acc as oral pres)
Sandler, H., DeSilvio, M., Pienta, K., Hug, E., Asbell, S., Rajan, R., Kerlin, K., Michalski, J. and Rosenthal, S.: Preliminary Analysis of RTOG 9902: Increased Toxicity Observed with the Use of Adjuvant Chemotherapy. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S123, Abs. #203, 2005.	9902 (acc as oral pres)
Fox, S., Berkey, B., Michalski, J., Purdy, J., Simpson, J., Kresl, J.J., Curran Jr, W., Diaz, A., Mehta, M. and Movsas, B.: Health-Related Quality of Life and Cognitive Status in Patients with Glioblastoma Multiforme Receiving Escalating Doses of Conformal Three-Dimensional Radiation on RTOG 9803. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S78, Abs. #128, 2005.	9803 (acc as oral pres)
Zempolich, K., Milash, B., Fuhrman, C., Robert, F., Greven, K., Ryu, J., Forbes, A., Kerlin, K., Nicholas, R. and Gaffney, D.: Changes in Gene Expression Induced by Chemoradiation in Advanced Cervical Carcinoma: A Microarray Study of RTOG C-0128. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S96, Abs. #159, 2005.	0128 (acc as oral pres)
Movsas, B., Moughan, J., Swann, S., Coyne, J., Konski, A., Komaki, R., Bradley, J., Langer, C., Choy, H. and Watkins Bruner, D.: Back to B.E.D. Predictors of Outcome in RTOG Non-Operative Non-Small Cell Lung Cancer (NSCLC) Trials. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S230-S231, Abs. #1139, 2005.	9801, 9410, 9015, 9103, 9106, 9204, 9205, 9304, 9311 (acc as poster disc)
Chakravarti, A., DeSilvio, M., Zhang, M., Grignon, D., Rosenthal, S., Asbell, S., Hanks, G., Sandler, H., Pollack, A., Zhai, G. and Shipley, W.: The Prognostic Value of p16 Expression in Locally Advanced Prostate Cancer: A Study Based on RTOG 92-02. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S17-S18, Abs. #30, 2005.	9202 (acc as oral pres)
Pollack, A., DeSilvio, M., Khor, L.-Y., Hammond, E., Al-Saleem, T., Grignon, D., Che, M., Varagur, V., Byhardt, R., Rotman, M., Hanks, G. and Sandler, H.: MDM2 Expression Is Independent of P53 and Ki-67 in Predicting Prostate Cancer Outcome: An Analysis of RTOG 92-02. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S17, Abs. #29, 2005.	9202 (acc as oral pres)
Choy, H., Swann, S., Curran, W., Whipple, G., Demas, W. and Ettinger, D.: A Phase I Trial of Gemcitabine, Carboplatin or Gemcitabine, Paclitaxel and Concurrent Radiation Therapy Followed by Consolidative Gemcitabine and Carboplatin for Inoperable Stage III Non-Small Cell Lung Cancer: An RTOG 0017 Study. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S42-S43, Abs. #70, 2005.	0017 (acc as oral pres)
Bradley, J., Deasy, J., Naqa, I.E., Lindsay, P., Hope, A., Bosch, W., Matthews, J., Sause, W. and Graham, M.: Predictors of Lung Toxicity from the RTOG 9311 Radiation Dose Escalation Trial: GTV Position is Important. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S40-S41, Abs. #67, 2005.	9311 (acc as oral pres)
Machtay, M., Swann, S., Komaki, R., Byhardt, R., Paulus, R., Sause, W., Albain, K.S., Movsas, B. and Curran Jr, W.: Higher BED is Associated with Improved Local-regional Control and Survival for NSCLC Treated with Chemoradiotherapy: An RTOG Analysis. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S40, Abs. #66, 2005.	8808,9015,9106,9204,9309,9410,9801 (acc as oral pres)
Lawton, C., DeSilvio, M., Roach III, M., Uhl, V., Krisch, R., Seider, M., Rotman, M., Jones, C., Asbell, S., Valicenti, R., Han, S. and Thomas, C.: 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. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S19, Abs. #32, 2005.	9413 (acc as oral pres)
Swanson, G., Thompson, I., Tangen, C., Miller, G., Lucia, M.S., Troyer, D., Paradelo, J., Chin, J., Messing, E., Canby-Hagino, E., Forman, J. and Crawford, E.D.: Phase III Randomized Study of Adjuvant Radiation Therapy versus Observation in Patients with Pathologic T3 Prostate Cancer (SWOG 8794). Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S1, Abs. #1, 2005.	9019 (acc as plenary pres)

Miscellaneous
Young, B., Swann, S., Berkey, B., Motyka-Welsh, E., Caldwell, T. and King, S.: Enhancing the Organizational Efficiency of The Radiation Therapy Oncology Group Through a Continuous Quality Improvement Initiative. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S385-S386, Abs. #2266, 2005.	N/A (acc as poster pres)

Langer, C., Swann, S., Curran Jr, W., Movsas, B., Werner-Wasik, M., Komaki, R., Lee, J.S. and Choy, H.: Reassessing Prognostic Factors in the Era of Combined Modality Therapy for Locally Advanced NSCLC: A Retrospective Analysis of RTOG 9410 and 9801. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S39-S40, Abs. #65, 2005. Purpose/Objective: Standard stratification criteria in studies evaluating patients with locally advanced non-small cell lung carcinoma (LA-NSCLC) generally include gender, stage, occasionally age and histology. However, we need to conduct contemporary analyses of more recent trials in LA-NSCLC to determine if these factors are still prognostic. Materials/Methods: We evaluated the baseline demographics of two separate phase III trials. RTOG 9410, a randomized phase III trial in good prognosis LA-NSCLC, compared sequential cisplatin-based chemotherapy followed by radiation (63 Gy) to concurrent chemotherapy and once daily radiation (63 Gy) or concurrent chemotherapy and twice daily RT (69.6 Gy); the platinum dose in each arm was equivalent. RTOG 9801 evaluated induction chemotherapy with paclitaxel and carboplatin followed by concurrent BID RT, weekly paclitaxel and carboplatin ± amifostine. We assessed the distribution of prognostic covariates in each study, and then analyzed hazard ratios, confidence intervals and p values, for each potential prognostic factor, including age, stage, T & N status, histology, gender, KPS, tumor location, and hemoglobin. Results: 805 evaluable patients were accrued: 576 on RTOG 9410; 229 on RTOG 9801. 82% were <70 yo; 57% had stage IIIB NSCLC; 37% had squamous histology. 64% were male. 17% had N0/1 disease, 55% N2, and 28% N3. KPS was 90-100 in 75%. 21% had primary tumor location in the lower lobes. Baseline median hemoglobin was 13.4; 17% had baseline hemoglobin below 12. At this point 160 patients (20% of the total enrollment) remain alive; 10% of those enrolled in 9410 at a median f/u of 6.1 yrs and 45% of those on 9801 with a median f/u of 1.1 yrs. By Cox modeling, N Stage as a categorical variable (N0 vs N1 vs N2 vs N3), KPS (90-100 vs 70-80) and tumor location (lower lobe versus other) were prognostic, with p values of 0.0002; 0.0003, and 0.0043 respectively. In 9410, these three factors were still prognostic, as was histology: pts with non-squamous histology fared better (p=0.0336). In 9801, the histologic disparities were no longer operative. 55 (7%) had 0-1 poor prognostic factors, 405 (52%) had 2 or 3, 315 (41%) more than 3. By Cox modeling, those with 2 or 3 poor prognostic factors had a hazard ratio (HR) of death of 1.42 (CI: 1.01-1.99; p=0.0418), and those with > 3 had a HR of 1.9 (CI: 1.35-2.67; p=0.0002). Relative median survivals were 21.6 mos, 16.5 mos, and 12.8 mos. Conclusions: Prognostic modeling in locally advanced NSCLC, in the setting of non-operative combined modality therapy, is probably best performed by assessing multiple risk factors. Independently, KPS, tumor location, and N status, particularly in platinum-based RTOG trials, have proven prognostic. Observations from this analysis will likely form the basis of future stratifications in RTOG efforts targeting locally advanced NSCLC.

Komaki, R., Swann, S., Curran Jr, W., Robert, F., Werner-Wasik, M., Lee, C., Jafar, S., Share, R., Choy, H. and Blumenschein, G.: A Phase II Study of Cetuximab (C225) in Combination with Chemoradiation (CRT) in Patients (PTS) with Stage IIIA/B Non-Small Cell Lung Cancer (NSCLC): An Interim Overall Toxicity Report of the RTOG 0324 Trial. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S44, Abs. #72, 2005. Purpose/Objective: Cetuximab (C225) is a chimerized monoclonal antibody that targets the epidermal growth factor receptor (EGFR). NSCLC commonly overexpresses the EGFR, which is associated with aggressive tumor behavior and poor clinical outcome. Preclinical model systems demonstrate radiosensitization following molecular inhibition of EGFR signaling. An ongoing Phase II trial is testing cetuximab, with CRT, in unresectable stage III NSCLC. Materials/Methods: Eligibility criteria include Zubrod performance status (PS) <= 1, weight loss <= 5% over past 3 months, FEV1>= 1.2l, adequate hematologic, hepatic, and renal function. PTS start an initial dose of C225 (400 mg/m2) on day 1 of week 1, then weekly doses of C225 (250 mg/m2) until completion of therapy (weeks 2 - 17). During week 2, patients receive CRT (63 Gy/34 fractions) with weekly carboplatin (C) AUC 2 and paclitaxel (P) 45 mg/m2 × 7doses followed by C (AUC 6) and P (200 mg/m2) × 2 cycles (weeks 12-17). Interim monitoring for severe (grade >=3) or excessive non-hematologic toxicities will occur after PTS have been treated and followed for at least 90 days after RT. Endpoints include safety and compliance of concurrent C225 and CRT. Results: 57 PTS have been entered to date with toxicity data available on 29. PTS characteristics (n=47) 64% male, median age 64 years (range 42-85), 55% PS 0, 47% stage IIIA. Data on adverse events related to treatment (n=29): There were 16 (55%) Grade 3+ non-hematologic adverse events reported as definitely, probably or possibly related to treatment among 29 reported cases including 2 ineligible cases. One of the ineligible cases had Grade 5 pneumonitis. This patient was determined to be ineligible due to >5% weight loss. The other ineligible case reported Grade 3 fatigue, dermatitis exfoliative NOS, ataxia, syncope, and dyspnea. The sole Grade 4 non-hematologic adverse event was hypersensitivity NOS before the start of radiation therapy. Conclusions: Patient accrual is ongoing. Updated toxicities will be reported.

Pajak, T., Trotti, A., Gwede, C., Paulus, R., Cooper, J., Ridge, J.A., Fu, K. and Ang, K.K.: The TAME Risk Classification System: Acute Toxicity Burden and IPD Analysis of RTOG 90-03. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S131, Abs. #217, 2005. Purpose/Objective: There is no single standardized method for concisely summarizing and comparing aggregate adverse event (AE) data among clinical trials or treatment options. The traditional "Worst Grade" method reports only one event per patient per tissue category and thus systematically excludes 30-70% of high-grade adverse events (Trotti; Radium Society 2005). We propose a new concept ("toxicity burden"), and new metrics, to reflect treatment-related risk. Analogous to the T-N-M tumor staging system, the "T-A-M End-results system"(TAME) consolidates adverse effects data into a concise summary index: short-term (acute) toxicity T, adverse late effects A and mortality risk from treatment M. An average T-score reflects all the reported high-grade acute events experienced by a cohort. We recently reported estimated T-scores from published adverse event data in 2200 patients (13 treatment arms) from 5 RTOG H&N trials (90-03, 91-11, 95-01, 97-03, 99-14). This demonstrated more than a 500% increase in acute toxicity burden when comparing aggressive chemoradiotherapy to conventional radiotherapy (range: 0.47-3.14), generating acute toxicity burden risk classes: <0.69 (low), 0.7-0.99 (mod), 1.00-2.49 (high), >2.5 (extreme) (Trotti; ASCO 2005. Materials/Methods: We calculated the percent of "acute toxicity burden excluded" by the traditional Worst Grade method (the total number of high-grade 3+ events that were NOT counted) for the standard fractionation arm (SFX) (n=266) and accelerated fractionation concomitant boost (AFX-C) arm of the RTOG 90-03 trial (n=266). We calculated average cohort T-scores from individual patient data (IPD) and the distribution of individual patient T-scores for each arm. We correlated T-scores with KPS and selected QOL domains reported at one-month follow-up. Results: The Worst Grade method failed to report 29% of all high-grade events in SFX and 39% in AFX-C (table). IPD-based average T-score calculations suggest SFX (T=0.50) is in a "low burden" class and AFX-C (T=0.97) is in a "moderate" risk class of toxicity burden. There was a significant difference in T-score distributions between the arms (p<0.0001). Correlations of T-scores with post treatment KPS and selected QOL domains were modest as expected for both arms. Conclusions: In comparison to TAME, the Worst Grade method systematically underestimates acute toxicity burden. IPD-based T-scores (incorporating all recorded adverse events) indicate AFX-C generates twice as much acute toxicity burden as SFX. Acute toxicity risk classification for SFX is in the low range and is in the moderate range for AFX-C when compared to estimates from 5 other RTOG H&N trials. These analyses support the feasibility of quantifying and classifying the toxicity burden of different treatment options. TAME may have wide applications in clinical trial reporting/interpretation in multiple oncologic disorders including: more formal evaluation of the therapeutic index, selection of therapy for a given patient, real-time safety monitoring, and identification of patient groups at high risk for injury.

Horwitz, E., Harris, J., Langer, C., Nicolaou, N., Kies, M., Curran Jr, W., Wong, S. and Ang, K.K.: Phase II Study of Paclitaxel and Cisplatin in Combination with Split Course Concomitant Hyperfractionated Re-Irradiation in Patients with Recurrent Squamous Cell Cancer of the Head and Neck: Results of RTOG 99-11. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S72-S73, Abs. #119, 2005. Purpose/Objective: Treatment options are limited for patients, previously irradiated, with locally recurrent or second primary head & neck tumors (SPT). The median survival for patients treated with chemotherapy alone is 6-8 months and 1-yr survival rates are typically < 35%. Based on results from a Phase I study of split course hyperfractionated radiation therapy (RT) in combination with concurrent chemotherapy, the RTOG developed a Phase II study. We report results on all patients enrolled on RTOG 99-11, which assessed re-irradiation (RT) and concurrent chemotherapy. Materials/Methods: Eligibility stipulated recurrent squamous cell cancer of the head & neck or SPT within a previously radiated field; measurable tumor; 75% of tumor volume previously treated to 45 Gy-75 Gy; 6 months elapsed from prior RT, ECOG performance status 0-1, adequate marrow, hepatic, and renal function, and no evidence of distant metastases. Patients were treated with split course hyperfractionated RT (60 Gy total: 1.5 Gy/fraction BID × 5d every 2 weeks for 4 cycles), in combination with DDP 15 mg/m2 IV daily × 5 and paclitaxel 20 mg/m2 IV daily × 5 q 2 weeks for 4 cycles. G-CSF support was administered days 6 through 13 of each 2 week cycle. Results: 105 patients enrolled between 3/30/2000 and 6/6/2003, and 99 patients were eligible for analysis. 23% of the patients had SPT. The median age was 60, 76% were male and 66% had a performance status 1. Oropharynx (40%) and oral cavity (27%) were the predominant primary sites. Median prior RT dose was 65.4 Gy (range 45-75), and the median time from prior RT was 40 months. The median RT dose in this study was 60 Gy. 70% received RT per protocol or with acceptable variation and 74% received all 4 scheduled cycles of chemotherapy. Of 8 (8%) patients with grade 5 (fatal) toxicities, 5 occurred during the acute period (dehydration, pneumonitis, neutropenia 2 cases and CVA) and 3 during the late period (2/3 attributable to carotid hemorrhage). Grade 4 acute toxicity occurred in 23%. Other acute toxicities included 30% grade 3-4 leukopenia, 21% grade 3-4 anemia, and 48% grade 3-4 GI toxicity. 5% of the patients experienced delayed osteoradionecrosis. Median follow-up for alive patients is 23.6 months. Median survival is 12.1 months with estimated 1- and 2-year overall survival rates 50.2% (95% CI: 40.0, 59.6) and 25.9% (95% CI: 17.3, 35.3), respectively. Median and 1-year progression-free survival is 7.8 months and 35% (25.7, 44.4), respectively. Overall survival is significantly better (one-sided log-rank p= 0.044) than historical control RTOG 96-10 (estimated 1- and 2-year overall survival rates 41.7% and 16.7%, respectively), which treated patients with split course re-irradiation combined with hydroxyurea and 5-FU. Conclusions: Median and overall survival rates for patients treated on RTOG 99-11 exceed those of RTOG 96-10, a historical control which assessed combination re-irradiation and non-platinum chemotherapy. Despite significant toxicity, hyperfractionated split course re-irradiation with concurrent cisplatin and paclitaxel chemotherapy proved feasible and demonstrates promising results in this selected patient population. This approach will be tested in a RTOG phase III trial against chemotherapy only.

Gaffney, D., Winter, K., Dicker, A., Miller, B., Jhingran, A., Ryu, J., Avizonis, V.N., Fromm, M. and Greven, K.: A Phase I-II Study of COX-2 Inhibitor, Celebrex (Celecoxib) and Chemoradiation in Patients With Locally Advanced Cervical Cancer: Primary Endpoint Analysis of RTOG 0128. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S93-S94, Abs. #155, 2005. Purpose/Objective: To determine treatment related toxicity rates in patients with locally advanced cervical cancer treated by oral celecoxib, intravenous cisplatin and 5-FU, and concurrent pelvic radiation therapy. Materials/Methods: Eligible patients on this RTOG phase I-II study for advanced cervix cancer included FIGO stage IIB-IVA or patients with FIGO stage IB through IIA with biopsy proven pelvic node metastases or tumor size greater than 5 cm. Patients were treated with pelvic radiotherapy to a dose of 45 Gy in 25 fractions and either low dose rate brachytherapy times two or high dose rate brachytherapy times five. Celecoxib was prescribed at 400 mg twice daily beginning on day one for one year. Cisplatin (75mg/m2) and 5-FU (1g/m2 for 4 days) was administered every three weeks times three. The primary end point of the study was treatment related toxicity as defined by 1) grade 3/4 nausea, vomiting, or diarrhea despite medical intervention, 2) grade 4 neutropenia or leukopenia persisting for greater than seven days, 3) grade 3/4 thrombocytopenia and anemia and 4) grade 3/4 other toxicity including gastrointestinal, renal, cardiac, pulmonary, hepatic, and neurologic toxicity. The primary endpoint hypotheses assumed a treatment related toxicity rate of 22% with an alternative rate of greater than 35%, at which the treatment regimen would be considered excessively toxic. Based on the study design with a binomial distribution, alpha = 0.05 and 90% power, if 34 or more out of the first 75 evaluable patients experienced a treatment related toxicity, as defined above, the treatment regimen would be considered excessively toxic. Results: Between August 2001 and March 2004, 84 patients were accrued to the study and 77 patients were evaluable for toxicity. The median age was 45 years. The stage distributions were: IB 23%; IIA 4%; IIB 52%; IIIB 17%, and IVA 4%. Regarding the primary end point, toxicities were observed in the following areas: blood/bone marrow (16), gastrointestinal (12), pain (7), renal/genitourinary (6), cardiovascular (3), hemorrhage (1), and neurologic (1). For the first 75 evaluable patients, a toxicity failure was identified in 35 patients for a rate of 47%. This exceeded the upper limit of the toxicity boundary and, thus, the regimen was deemed excessively toxic. Additionally, for all grades 3 and 4 toxicities, the worst non-hematologic toxicity were observed in 53% and 13% of patients, respectively. Conclusions: Celecoxib at 400 mg twice daily together with concurrent cisplatin and 5-FU and pelvic radiotherapy is an excessively toxic regimen. Few of the toxicities were directly attributable to the celecoxib. The most frequent toxicities were hematologic. Given the excessive acute toxicity in this protocol, future advanced cervix cancer protocols within the RTOG will likely include single agent cisplatin plus an additional biologic agent. Albeit, the toxicity was deemed excessive in this trial, investigation with biologically targeted therapies is warranted for the treatment of advanced cervix cancer both in the concurrent chemoradiotherapy setting and for maintenance therapy post completion of chemoradiotherapy.

Small Jr, W., Winter, K., Levenback, C., Iyer, R., Gaffney, D., Asbell, S., Erickson, B. and Greven, K.: Extended Field Irradiation and Intracavitary Brachytherapy Combined with Cisplatin Chemotherapy for Cervical Cancer with Positive Para-aortic or High Common Iliac Lymph Nodes: Results of Arm 1 of RTOG 0116. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S94, Abs. #156, 2005. Purpose/Objective: Cervical cancer patients with para-aortic or high common iliac metastatic disease have traditionally been treated with extended field irradiation combined with brachytherapy. Given the results of randomized trials involving combined chemotherapy and pelvic radiotherapy in locally advanced pelvic disease, this combination should apply to patients necessitating extended field radiotherapy. Preliminary evidence suggests this is associated with significant toxicity. RTOG 0116 was designed to test the ability of Amifostine, a cytoprotective agent, to reduce the toxicity of combined chemotherapy with extended field radiotherapy and brachytherapy, after first determining the toxicity rate for the regimen without the Amifostine. This abstract reports the toxicity and outcome results for the treatment without Amifostine. Materials/Methods: RTOG 0116 was designed as a two-part trial. Part one delivered extended field irradiation and brachytherapy combined with weekly cisplatin chemotherapy, part two adds Amifostine. The two part design was utilized to obtain an accurate estimate of toxicity in part one from which to base the number of patients needed to be treated with Amifostine to demonstrate a reduction in toxicity. Eligibility included patients with squamous cell, adenocarcinoma or adenosquamous carcinoma of the cervix with evidence for high common iliac or para-aortic metastasis. Patients were treated with standard extended field radiotherapy from the T11/T12 interspace through the pelvis for a total dose of 45 Gy in 25 fractions, followed by intracavitary irradiation to a total point A dose of 85 Gy LDR equivalent. HDR was allowed. The positive para-aortic and high common iliac nodes were to be boosted to a total of 54 to 59.4 Gy at the investigator's discretion. Cisplatin at a dose of 40 mg/m2 was delivered weekly during external beam and once with brachytherapy. The primary endpoint of part one was acute grade 3 and 4 toxicity, excluding grade 3 leukopenia. Results: Twenty-seven patients were entered on trial between 8/01/2000 to 12/03/2003. One patient was ineligible. Twenty-one of the patients were noted to have para-aortic metastasis with the remaining having high common iliac metastasis. Follow-up ranged from 1.8 - 32.8 months with a median of 15.5 months. The acute grade 3 and 4 toxicity rate, excluding grade 3 leukopenia was 81%. Toxicity rates are shown in the table below. Four of the 5 patients with a grade 4 late toxicity were noted to have bowel complications necessitating surgical intervention. The final grade 4 toxicity was rectal bleeding to a hemoglobin of 3.8. Sixteen (61.5%) of the 26 patients had a complete response to therapy. The complete local response was 92.3% while the complete nodal response rate was 61.5%. Estimated disease free and overall survival at one year are 46% and 75% respectively. Conclusions: Extended field and intracavitary irradiation with cisplatin chemotherapy for para-aortic or high common iliac metastasis from cervical cancer is associated with significant acute and late toxicity. It is hoped that the addition of Amifostine in part two of the trial will be associated with reduced toxicity.

Konski, A., DeSilvio, M., Hartsell, W., Watkins-Bruner, D., Coyne, J., Scarantinio, C. and Janjan, N.: Continuing Evidence for Poorer Treatment Outcomes for Single Male Patients: Re-Treatment Data from RTOG 97-14. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S192, Abs. #1079, 2005. Purpose/Objective: The RTOG has previously reported outcome difference based upon socioeconomic factors, including marital/live-in status. Married or men with a live-in partner treated on 3 RTOG head and neck clinical trials had improved local control and overall survival compared to single men while this effect difference did not translate to women. RTOG 97-14 compared 30 Gy in 10 fractions to 8 Gy in 1 fraction in the treatment of patients with symptomatic bone metastases from breast and prostate cancer. The specific aim of this study is to evaluate outcome differences based upon marital status. Materials/Methods: RTOG 97-14 randomized patients with metastatic breast or prostate cancer to bone to receive 8 Gy in 1 fraction or 30 Gy in 10 fractions. Comparisons of re-treatment rates and overall survival were made based upon gender, marital status and Karnofsky Performance Status (KPS). The cumulative incidence method was used to estimate the time to re-treatment at 36 months and Grays test was used to test for treatment differences within the same groupings. Survival differences were evaluated by means of the log rank test. Marital status, gender, KPS and treatment were variables tested in a univariate Cox model evaluating the time to re-treatment. Results: Women and men receiving 30 Gy had a significantly longer time to re-treatment compared to patients receiving 8 Gy, p<0.0001 and p<0.026 respectively. Women lived significantly longer than men, regardless of treatment arm (median survival of females and males is 11.8 and 7.8 months, respectively, p<0.0001). Married men and women and single women receiving 30 Gy had significantly longer time to re-treatment, p=0.007, p=0.0052, and p=0.0009 respectively. We failed to show a difference in re-treatment rates in single men receiving either 30 Gy or 8 Gy. Re-treatment rates were higher in married and single women receiving 8 Gy regardless of KPS while only men with initial KPS of 70-80 had fewer re-treatments from 30 Gy. Univariate analysis of the entire group determined patients receiving 30 Gy in 10 fractions significantly less likely to receive re-treatment, p<0.0001, with a trend towards single patients not receiving re-treatment, p=0.07. Conclusions: Non-disease related variables, like social support, might influence the results of clinical trials with subjective end-points such as re-treatment rates. The lower re-treatment rates observed in single male patients receiving 8 Gy may be a result of the lack of adequate social support systems in place to facilitate additional care. Clinicians may need to be sensitive to the greater likelihood of negative outcomes in single male patients but more focused strategies depend on better specification of what aspects of being single are most disadvantageous to men with cancer.

Garden, A., Harris, J., Jones, C., Trotti, A., Carrascosa, L., Cheng, J., Spencer, S., Weber, R. and Ang, K.K.: Concomitant Boost Radiation and Concurrent Cisplatin for Advanced Head and Neck Carcinomas: Update of a Phase II Trial of the RTOG (99-14). Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S71-S72, Abs. #117, 2005. Purpose/Objective: To update the results of a phase II trial that was undertaken to assess the toxicity, local-regional (LR) control, and survival of the combination of accelerated fractionation by concomitant boost (AFX-CB) and concurrent cisplatin for the treatment of patients with locally advanced head and neck carcinomas (HNC). Materials/Methods: Between April and November 2000, 84 patients with histologic proof of stage III or IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and having Zubrod performance status of 0-1 and adequate hematologic, hepatic, and renal functions were enrolled on this protocol; 76 were analyzable. The median age of the study population was 57 (range 40-76) years, 60 (79%) patients were men, 50 (66%) had oropharyngeal cancer, 67 (88%) had stage IV disease. The radiation dose was 72 Gy in 42 fractions over 6 weeks, delivered in one daily fraction of 1.8 Gy during the first 3.5 weeks and two fractions per day, 1.8 Gy and 1.5 Gy separated by >=6 h interval, during the last 2.5 weeks. Cisplatin, 100 mg/m2, was given in short iv infusion for two courses at week 1 and week 4 or 5. The acute toxicity and preliminary results were reported (Ang et al., J Clin Oncol, In Press). The data of 51 patients who were alive at previous analysis have been updated for this report. Actuarial rates were estimated by the Kaplan-Meier method. Results: The median follow-up is 2.8 years for all patients and 3.9 years for 43 patients alive. Cause of death was index cancer in 25 patients, treatment complications in 3, and other or unspecified causes in 5. The estimated 3-year disease-free, overall, and cause-specific survival rates are 45.8%, 57.7%, and 61.2% respectively. The estimated 3-year LR failure and distant metastases rates are 38.7% and 23.3%, respectively. The estimated 3-year incidence of late (occurring >180 days from start of radiation) grade 3-4 toxicities is 46.8%. Of the 35 patients alive with no evidence of disease, 22 (62.9%) had a temporary feeding tube for nutritional support, and 6 (17.1%) still had a feeding tube at their most recent follow-up visit. The estimated 1- and 3-year feeding tube use rates are 32.8% and 13.5%, respectively. Conclusions: This phase II study was launched to test the combination of AFX-CB, shown in a previous RTOG phase III trial to significantly reduce LR failure as compared to standard once-a-day radiation, with cisplatin in patients with advanced HNC. This updated analysis showed that the combined regimen yielded very encouraging overall survival, cause-specific survival, and local-regional control rates compared with those observed previously with altered fractionation regimens but the distant metastasis rate remained within the same range. However, the addition of cisplatin to AFX-CB also appeared to increase long-term toxicity. Whether the therapeutic index of AFX-CB is superior to standard fractionation when combined with concurrent cisplatin is being addressed in an ongoing RTOG trial (0129). The observation that local-regional relapse is still the leading pattern of failure demonstrates the need to assess the role of treatment intensification, such as integrating biologic therapy with concurrent radiation and chemotherapy.

Zhang, M., Ho, A., Hammond, E., Roach III, M., Sause, W., Pilepich, M., Shipley, W., Sandler, H., Pollack, A. and Chakravarti, A.: The Prognostic Value of Surviving in Locally Advanced Prostate Cancer: A Study Based on RTOG 8610. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S18, Abs. #31, 2005. Purpose/Objective: Survivin is a member of the inhibitor of apoptosis family that has been implicated in both control of apoptosis and regulation of cell division. Growing evidence suggests that nuclear Survivin expression may represent an important prognostic marker to predict disease outcome for cancer patients. Current reports in this field, however, are controversial and propose opposing conclusions regarding the significance and prognostic value of nuclear Survivin expression. To our knowledge, no study has previously examined the predictive value of nuclear Survivin expression in men with prostate cancer. We examined the association between nuclear Survivin expression and overall survival, prostate cancer survival, distant metastasis, and local progression in men treated with radiotherapy (RT) alone or RT + short term androgen deprivation (STAD) who were enrolled in Radiation Therapy Oncology Group (RTOG) protocol 8610. Materials/Methods: Of the 456 eligible and analyzable cases (parent cohort), 68 patients had adequate and suitably-stained tumor material for nuclear Survivin analysis (Survivin cohort). Of these, 38 were randomized to RT alone and to RT+STAD. Pretreatment characteristics of the parent and Survivin cohorts were not statistically different. Expression levels of nuclear Survivin were determined by immunohistochemical staining (DAKO Envision+, DakoCytomation, Carpinteria, CA) using anti-Survivin polyclonal antibody (Novus Biologicals, Littleton, CO). An image-analysis system (ACIS, Chromavision Medical Systems, San Juan Capistrano, CA) was used to measure the percentage of cells with nuclear staining and the intensity of nuclear staining. The five-year actuarial estimates for overall and prostate cancer survival were calculated using the Kaplan-Meier method and the cumulative incidence method was used to estimate the five-year local progression and distant metastasis failure rates. The univariate analyses were done using Survivin ACIS Mean Index % as a continuous variable and an additional cutpoint of a median, <=74.1 vs. >74.1, or using Survivin ACIS Intensity Score as a continuous variable and an additional cutpoint of median, <=191.2 vs. >191.2. Moreover, Survivin ACIS Mean Index % was modeled in multivariate analysis using Cox proportional hazards models to identify the impact of nuclear Survivin on the four endpoints in the presence of other covariates such as Gleason score, clinical stage, and assigned treatment. Results: Higher levels of nuclear Survivin appeared to be associated with improved outcome in this patient population. Our analysis indicated that the cutpoint intensity score of 191.2 was most informative in this regard. Compared to those with Survivin ACIS Intensity Score <=191.2, those who had Survivin ACIS Intensity Score >191.2 showed a significantly improved prostate cancer survival with a p-value of 0.05 (relative risk=0.45). On multivariate analysis, Survivin ACIS Intensity Score >191.2 was significantly associated with improved overall survival (p=0.02) and prostate cancer survival (p=0.02). Conclusions: Nuclear Survivin ACIS scores of >191.2 were associated with improved overall and prostate cancer survivals on multivariate analysis in patients with locally advanced prostate cancer treated on RTOG 8610. A separate analysis of the prognostic value of cytoplasmic Survivin expression is ongoing.

Zhai, G., Ho, A., Hammond, E., Fontanesi, J., Rotman, M., Pilepich, M., Shipley, W., Sandler, H., Pollack, A., Zhang, H. and Chakravarti, A.: Phospho-AKT Expression and Prognosis of Locally Advanced Prostate Cancer: A Study Based on RTOG 8610. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S319, Abs. #2152, 2005. Purpose/Objective: Preclinical models suggest that activation of PI3K/serine-threonine kinase AKT pathway promotes cell survival and potentially treatment resistance in several tumor types. To our knowledge, no study has previously examined the prognostic value of phospho-AKT expression in men with prostate cancer who have been treated with RT ± AD. We examined the association between phospho-AKT expression and overall survival, prostate cancer survival, distant metastasis, and local progression in men treated with RT alone or RT + short term androgen deprivation (STAD) who were enrolled in Radiation Therapy Oncology Group (RTOG) protocol 8610. Materials/Methods: Of the 456 eligible and analyzable cases (parent cohort), 80 patients had adequate and suitably-stained tumor material for phospho-AKT analysis (AKT cohort). Of these, 47 were randomized to RT alone and 33 to RT+STAD. Pretreatment characteristics of the parent and AKT cohorts were not statistically different. Expression levels of phospho-AKT were determined by immunohistochemical staining (DAKO Envision+, DakoCytomation, Carpinteria, CA) using anti-phospho-AKT antibody (Cell Signaling, Beverly, MA), and reviewed under light microscopy for measuring the percentage of cells with positive staining and the intensity of the staining. The five-year actuarial estimates for overall and prostate cancer survival were calculated using the Kaplan-Meier method and the cumulative incidence method was used to estimate the five-year local progression and distant metastasis failure rates. The univariate analyses were done using phospho-AKT Mean Index % as a continuous variable and four additional cutpoints of <5 vs. >=5, >25 vs. >=25, <50 vs. >=50, and a median <=70 vs. >70, or using phospho-AKT Intensity Score as a continuous variable and an additional cutpoint of 0 vs. >=1. Moreover, phospho-AKT Mean Index % was modeled in multivariate analysis using Cox proportional hazards models to identify the impact of AKT expression on the four endpoints in the presence of other covariates such as Gleason score, clinical stage, and assigned treatment. Results: None of the analytic results from the univariate models of the four endpoints demonstrated a statistically significant association with phospho-AKT score. Although the relative risk (RR) in local progression increased as phospho-AKT Mean Index % increased (RR = 1.04, 1.10, 1.26, and 1.56 for cutpoints 5, 25, 50, and 70, respectively), all the associations are non-significant. Of all the cutpoints of phospho-AKT Mean Index %, cutpoint of median (<=70 vs. >70) showed consistently increased relative risks of at least 20% for all the 4 endpoints as phospho-AKT Mean Index % increased. In multivariate analysis using the same cutpoint of a median (<=70 vs. >70), increased phospho-AKT Mean Index % still had 32 to 57% increases of relative risks for all the 4 endpoints when other factors such as Gleason score, clinical stage, assigned treatment were considered in the model. However, these increased risks were not statistically significant. Conclusions: Expression of phospho-AKT was not found to be a significant, independent prognostic marker in our relatively small cohort of patients with locally advanced prostate cancer who were treated primarily with radiation therapy ± androgen deprivation.

Trotti, A., Fu, K., Pajak, T., Jones, C.U., Spencer, S.A., Phillips, T.L., Garden, A.S., Ridge, J.A., Cooper, J.S. and Ang, K.: Long Term Outcomes of RTOG 90-03: A Comparison of Hyperfractionation and Two Variants of Accelerated Fractionation to Standard Fractionation Radiotherapy for Head and Neck Squamous Cell Carcinoma. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S70-S71, Abs. #116, 2005. Purpose/Objective: We previously reported two-year results demonstrating the superiority of hyperfractionation and concomitant boost schedules over standard radiotherapy. We now report 5-year outcomes from RTOG 90-03. Materials/Methods: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation (SFX) 2) hyperfractionation (HFX) 3) accelerated fractionation with split (AFX-S) or 4) accelerated fractionation with concomitant boost (AFX-C). Of the 1113 patients entered, 1073 patients were analyzable for outcomes. The median follow-up was 1.8 years for all analyzable patients and 5.3 years for patients still alive. Results: Patients treated with HFX and AFX-C regimens had significantly better 5-year local-regional control (p=0.037 and p= 0.042 respectively) than those treated with SFX. They experienced improved disease-free survival with them (p=0.013 and p=0.042 respectively). There was a trend toward improved overall survival in patients treated with hyperfractionation (p=0.063); there was no significant difference in cause-specific survival. There were no significant differences in the incidence of distant metastasis. Toxicity occurring within 180 days from the start of radiation was considered to be acute and beyond that, late. All three altered fractionation arms showed a significantly higher crude incidence of patients with grade 3+ acute side effects when compared to SFX. There was a trend toward an increased crude incidence of grade 3+ late effects with AFX-C compared to SFX (33.3% vs. 25.2%, p=0.066), but the incidences for HFX and AFX-S arm were similar to SFX. (27.4% and 26.8%) Conclusions: Five year results of hyperfractionation and accelerated fractionation with concomitant boost demonstrate superiority over standard fractionation for locally advanced head and neck cancer. Acute effects were increased in altered fractionation schedules and there was a slightly higher incidence of late effects with the concomitant boost schedule. Data will be updated for ASTRO 2005 with a potential 8-year median follow-up for the patients still alive.

Sandler, H., DeSilvio, M., Pienta, K., Hug, E., Asbell, S., Rajan, R., Kerlin, K., Michalski, J. and Rosenthal, S.: Preliminary Analysis of RTOG 9902: Increased Toxicity Observed with the Use of Adjuvant Chemotherapy. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S123, Abs. #203, 2005. Purpose/Objective: High risk, clinically localized prostate cancer (PCa) is generally treated with a combination of radiotherapy (RT) and long term, androgen ablation (LTAD). However, many patients (Pts) develop recurrence following therapy, ultimately with distant disease. Cytotoxic chemotherapy (CT) is beginning to have a larger clinical role in management of hormone refractory prostate cancer (HRPCa) and it was our hypothesis that adjuvant CT would improve the survival rate of high risk PCa when used in combination with RT and LTAD. Materials/Methods: Pts with PSA 20-100 and Gleason score (GS) >=7 or clinical stage >=T2 and GS >=8 were randomized to androgen ablation for 8 weeks then RT and LTAD with or without four 21-day cycles of CT with oral estramustine 280 mg tid × 14 days, oral VP-16 50 mg/m2 in divided doses bid × 14 days, and paclitaxel 135 mg/m2 iv on day 2. Warfarin was originally given at 1 mg/day during CT, but, after thromboembolic (TE) toxicity was observed, the dosage was increased to keep the INR between 1.5 and 2.5. The RT consisted of 46.8 Gy to a small pelvic field (in order to minimize hematologic toxicity) followed by a boost to the prostate of 23.4 Gy for a total dose of 70.2 Gy. Results: This study opened on Jan 11, 2000 and closed on Oct 4, 2004 with a total of 397 Pts (of a planned 1440) entered. Pts had high risk features: 68% had GS 8 or greater, median PSA was 22.7 ng/mL, and 33% were cT3. 378 Pts have toxicity information available. 199 Pts were enrolled with less intense anticoagulation and 179 Pts were enrolled after the anticoagulation was intensified. After the warfarin was increased, toxicity information was carefully scrutinized and the rate of TE event was found to exceed the rate prospectively defined as the maximum allowable (2 TE events occurred among first 10 eligible and analyzable Pts). This information was reported to the DMC and patient accrual was suspended on Jul 30, 2004 and permanently closed to patient accrual on Oct 4, 2004 for patient safety. Overall, there were 34 Pts who experience at least one grade >=4 events (2 grade 5) in the CT arm vs. 0 in the no-CT arm. Using Kaplan-Meier analysis and log rank testing, there were statistically significant increases in grade >=3 GI, cardiovascular, and TE toxicities in the CT arm. In the CT arm, the 12 month cumulative estimate of cardiovascular toxicity was 12% and, for TE events, it was 10%. For those Pts who actually received CT, the 1-yr rate of TE toxicity was 16% with less intense anticoagulation and 8% with more intense anticoagulation. Conclusions: Increased toxicity was seen in the CT arm of RTOG 9902. Careful monitoring led to an appropriate halt in patient accrual. Despite the early stoppage due to toxicity, this trial of nearly 400 Pts is the largest prospective chemotherapy-radiotherapy study in PCa and demonstrates that the RTOG can carry out CT trials in localized prostate cancer. Estramustine is associated with TE toxicity, which led to the early stoppage of this trial. Recent studies in HRPCa seem to indicate that this agent no longer needs to be a part of chemotherapy regimens for PCa. The RTOG will follow patients enrolled in this trial for outcome and longer term toxicity analysis. A successor trial (RTOG 0521) will be activated in high risk, localized PCa utilizing docetaxel without estramustine in order for further evaluate the hypothesis that adjuvant CT can improve survival in high risk, but clinically and radiographically non-metastatic PCa.

Fox, S., Berkey, B., Michalski, J., Purdy, J., Simpson, J., Kresl, J.J., Curran Jr, W., Diaz, A., Mehta, M. and Movsas, B.: Health-Related Quality of Life and Cognitive Status in Patients with Glioblastoma Multiforme Receiving Escalating Doses of Conformal Three-Dimensional Radiation on RTOG 9803. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S78, Abs. #128, 2005. Purpose/Objective: To determine the differences in cognitive status and health-related quality of life (HRQOL), and their effects on short-term survival, in patients with supratentorial glioblastoma multiforme (GBM) receiving three-dimensional conformal radiation therapy (3D-CRT). Materials/Methods: RTOG 9803 is a phase I/II trial that evaluated feasibility and toxicity of escalating doses of 3D-CRT delivered with bis-chlorethyl nitrosourea (BCNU) chemotherapy (CT) in patients with GBM. Doses were escalated from 66 to 84 Gy within groups of patients having planning target volumes (PTV) of either <75 cc or > 75 cc. Primary results of RTOG-9803 have been previously reported. This longitudinal analysis focuses on cognitive status as assessed with the Mini Mental Status Exam (MMSE)(Folstein, Folstein, McHugh, 1975) and health-related quality of life (HRQOL) as measured by the Quality of Life Index (QL-Index)(Spitzer, Dobson & Hall, 1981). Paired t tests were used to compare MMSE and HRQOL scores between baseline and follow-up at 3 months within each PTV group and dose subset. A Bonferroini adjustment for multiple comparisons was used to set a 0.025 significance level for these comparisons. A Cox regression model was used to analyze effects of baseline HRQOL and cognitive status on survival. Results: Of 203 eligible patients in the study, 200 (98.5%) had either MMSE (n=199) or Spitzer scores (n=185) at baseline. One hundred forty-eight (72.9%) had complete data at baseline and 3 months on either the MMSE (n=144) or Spitzer (n=132). The median age was 53.5. Patient pre-treatment characteristics were equally balanced between the two PTV cohorts with a majority of patients in each group having scores within the normal range on the MMSE (25-30), KPS scores of 80-100, and minor neurologic symptoms. Both baseline HRQOL (p=0.002) and MMSE (p<0.001) were predictive of survival in separate Cox models with covariates of PTV and assigned dose. With both scores in one model, MMSE was significant (p<0.001) and HRQOL was not. The patients in the PTV > 75cc group (n=63) had a trend toward decreased HRQOL at 3 months (means of 7.92 at baseline and 7.29 at 3 months, p=.03). When the possible relationships between the escalating doses of radiation and changes in cognitive status or HRQOL scores were examined at 3 months, persons in the PTV > 75 cc group had significant changes in cognitive status between baseline and 3 months at 66 Gy (n=22) (26.4 baseline Vs. 27.6, p<=.001) and at 84 Gy (n=11) (28.0 at baseline Vs. 26.0, p=.04). Conclusions: Baseline HRQOL and cognitive status have prognostic value for survival, suggesting continued evaluation of such outcomes is important in clinical trials and that early intervention to promote or conserve cognitive status and HRQOL are of critical importance. The decrease in the HRQOL scores at 3 months in patients with a larger PTV is not unexpected due to the effects of a large tumor burden, as well as the side effects of combined radiation and chemotherapy.

Zempolich, K., Milash, B., Fuhrman, C., Robert, F., Greven, K., Ryu, J., Forbes, A., Kerlin, K., Nicholas, R. and Gaffney, D.: Changes in Gene Expression Induced by Chemoradiation in Advanced Cervical Carcinoma: A Microarray Study of RTOG C-0128. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S96, Abs. #159, 2005. Purpose/Objective: To evaluate gene expression patterns in patients with advanced cervix cancer before and during chemoradiation in a multi-institutional cooperative group setting. Materials/Methods: RTOG C0128 was designed to look at the safety and efficacy of radiation therapy with concomitant 5-FU and cisplatin chemotherapy, and Celecoxib at 400 mg twice daily for one year. Patients had the option of participating in a tissue collection portion of the protocol to be utilized for micro-array gene expression analysis before treatment and at the time of the first implant (paired sample). RNA was extracted, linearly amplified, and purity was assessed by gel electrophoresis. Each sample was hybridized against a universal RNA mixture on a customized spotted array consisting of > 10,000 genes. We compared gene expression profiles with pre-treatment characteristics (FIGO stage, age, race, and histology), and changes with chemoradiation in individual patients. Data were normalized using the AROMA software, and clustering analysis was performed using Ward's method in Spotfire. Differences in paired samples were calculated with Significance Analysis of Microarrays (SAM). Results: From August 2001 to March 2004, 84 patients were accrued to the trial, and tissue was obtained prior to initiation of therapy on 34 patients (40%). FIGO stages for the patients who provided tissue were IB (23%), II (57%), and IIIA-IVA (20%). RNA quality was sufficient to proceed to microarray analysis in 22 pre-treatment and 14 post-treatment samples. Gene expression profiles were correlated to pre-treatment characteristics. No significant differences were observed by FIGO stage, age, or race; however, histology (adenocarcinoma, n=5, versus squamous cell carcinoma, n=17) yielded 45 genes differentially expressed with a false discovery rate of 0.018. Cluster analysis segregated unpaired samples into 2 groups; 18 of 22 samples comprising pre-treatment samples and 10 of 14 in the other group representing post-treatment samples. Among 13 paired samples, gene expression after chemoradiation was upregulated in 91 genes and down regulated in 251 genes, with a false discovery rate of 0.0018. Genes significantly upregulated included bax, cdk inhibitor 1, MMP2, and adhesion molecules PECAM1, VCAM1, and ICAM2. Genes significantly downregulated included topoisomerase II alpha, myc, H2AX, MSH2, RAD51, RAD53, PCNA, and cell cycle-regulating molecules chk1, CDK2, cyclinB1, cyclin D3, cdc2, and cdc25. Conclusions: Microarray analysis was successfully performed in a multinational cooperative group trial. Patterns of gene expression significantly correlated with histologic subtype, but not stage, age or race. Cluster analysis identified two groups of gene expression profiles correlating with pre or post-treatment acquisition of tissue. Notably, paired samples showed significant changes in gene expression following chemoradiation. Quantitative PCR can be utilized to confirm these changes in gene expression. Further analysis comparing gene expression to clinical outcomes, acute and late toxicities awaits maturation of clinical data. Hopefully, this information will lead to targeted therapy based on expression profiles.

Movsas, B., Moughan, J., Swann, S., Coyne, J., Konski, A., Komaki, R., Bradley, J., Langer, C., Choy, H. and Watkins Bruner, D.: Back to B.E.D. Predictors of Outcome in RTOG Non-Operative Non-Small Cell Lung Cancer (NSCLC) Trials. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S230-S231, Abs. #1139, 2005. Purpose/Objective: To analyze the influence of pre-treatment characteristics, socio-demographic variables and treatment factors on overall survival (OS), progression-free survival (PFS) and local-regional failure (LRF) in Radiation Therapy Oncology Group (RTOG) non-operative NSCLC trials activated during the 1990's. Materials/Methods: This secondary analysis is based on data from 1450 patients treated on nine prospective RTOG non-operative NSCLC studies activated during the 1990's. Studies included RTOG 9015, 9103, 9106, 9204, 9205, 9304 (RT arm only), 9311, 9410 and 9801. Six stratification levels based on the presence of chemotherapy (yes vs. no) and accrual year (1991-1994, 1995-1998, 1999-2002) were defined. Univariate regression models for outcome measures were built on the following variables controlling for strata: age, gender, race, KPS, weight loss, stage, histology, location of primary tumor, biological equivalent dose(BED)based on actual RT delivered, deviation from protocol dose (<95% vs. >=95%), marital status, education level, number of persons in household, family/friends with cancer, employment status, and household income (adjusted to 2002 dollars). Results: On univariate analysis, all variables, except for race, had significant prognostic impact on OS. On multivariate analysis, the following factors significantly predicted for lower OS: increased age (p=0.008), weight loss (p=0.006), squamous histology (p=0.025), higher stage (p=0.0004), lower lobe primary location (p=0.001), lower BED (p=0.0001), deviation (<95%)of total dose (p=0.0001), and 'high school education (p=0.0007). For PFS, the same factors were predictive, with the addition of male gender (p=0.003), but not age or histology. Predictors for LRF were similar to OS, with the addition of male gender (p=0.004), but not weight loss or deviations of total dose. The interaction of KPS and weight loss was predictive for both OS and PFS. Conclusions: Higher stage disease, higher education, lower lobe primaries and a lower BED significantly predicted for lower OS & PFS, and higher LRF after controlling for the other variables in the model. The only socio-economic factor predictive of outcome was education, requiring further study. For an increase in BED of 10 Gy, there was a dramatic reduction in the hazard of death by 14%; for an increase of 20 Gy, the reduction was 26%, suggesting the importance of escalating beyond current BED levels to improve outcome for patients with inoperable NSCLC.

Chakravarti, A., DeSilvio, M., Zhang, M., Grignon, D., Rosenthal, S., Asbell, S., Hanks, G., Sandler, H., Pollack, A., Zhai, G. and Shipley, W.: The Prognostic Value of p16 Expression in Locally Advanced Prostate Cancer: A Study Based on RTOG 92-02. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S17-S18, Abs. #30, 2005. Purpose/Objective: The retinoblastoma (RB) pathway is known to be deregulated in virtually all known human tumors. p16, the upstream regulator of RB, is among the most commonly affected members of this pathway. Previously we reported that loss of p16 expression was associated with adverse clinical outcome (J.Clin. Oncol., 21:3328-34, 2003). In the present study, we examined the prognostic value of p16 expression in men with locally advanced prostate cancer who were enrolled on RTOG 9202. Materials/Methods: Of the 1514 eligible cases, 612 patients had adequate tumor material for p16 analysis. Of these, 327 were randomized to LTAD (long-term androgen deprivation)+RT and 285 were randomized to STAD (short-term androgen deprivation) +RT. Expression levels of p16 were determined by immunohistochemical staining using anti-p16 antibody (Santa Cruz Biotechnology). An image-analysis system (ACIS, Chromavision) was used to measure the percentage of cells with nuclear staining. p16 mean index % was dichotomized as (1) <=81.3% (percent positive staining, PPV) vs. >81.3% PPV, (2) <=20% (PPV)vs. >20%. Cox proportional hazards models were utilized to identify the impact of p16 expression as both a continuous and categorical variable to overall survival, prostate cancer survival, distant metastasis, local progression, and biochemical progression. Actuarial estimates for overall and prostate cancer survival were calculated using the Kaplan-Meier method and the cumulative incidence method was used to estimate the local progression, distant metastasis, and biochemical progression failure rates. Results: On multivariate analysis, after adjusting for pretreatment clinical characteristics and assigned treatment, p16 mean index > 81.3% (higher levels of p16) was statistically significantly associated with decreased rate of distant metastases (hazard ratio= 0.60, 95% confidence intervals= 0.38 to 0.96, p= 0.0332). The multivariate analysis of assigned treatment by p16 index revealed that for patients with a mean p16 index > 81.3%, LTAD+RT significantly improved prostate cancer survival (PCS) over STAD+RT (unadjusted 5-year PCS: 97.8% vs. 89.2%, respectively, p=0.0008) and reduced the frequency of distant metastasis DM (unadjusted 5-year rate of DM: 7% vs. 16%, respectively, p=0.0069) over STAD+RT. In contrast, for patients with tumors demonstrating a mean p16 index <=81.3%, LTAD+RT failed to improve these outcome parameters compared to STAD+RT, but did appear to decrease the frequency of local progression (p=0.02). Further, within the LTAD+RT arm, patients with tumors demonstrating a mean p16 index > 81.3% compared to <=81.3% were found to have improved prostate cancer survival (unadjusted 5-year PCS: 97.8% vs. 94.1%, respectively, p=0.05) and reduced frequency of distant metastasis (unadjusted 5-year rates: 7.0% vs. 13.0%, respectively, p=0.02). p16 mean index did not appear to be of prognostic value within the STAD+RT arm. Conclusions: p16 mean index % <=81.3% (indicating a greater degree of p16 loss) on ACIS appears to be significantly associated with higher risk of distant metastases on multivariate analysis in patients with locally advanced prostate cancer who were treated on RTOG 92-02. The patients who appeared to derive the greatest benefit from LTAD+RT were those with tumors demonstrating higher levels of p16 expression (e.g. a mean p16 value of >81.3%).

Pollack, A., DeSilvio, M., Khor, L.-Y., Hammond, E., Al-Saleem, T., Grignon, D., Che, M., Varagur, V., Byhardt, R., Rotman, M., Hanks, G. and Sandler, H.: MDM2 Expression Is Independent of P53 and Ki-67 in Predicting Prostate Cancer Outcome: An Analysis of RTOG 92-02. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S17, Abs. #29, 2005. Purpose/Objective: MDM2 is a feedback regulator of p53. Both of these proteins are intimately involved in the regulation of apoptosis in response to radiotherapy (RT) ± androgen deprivation (AD). In this report we investigate the utility of the abnormal expression of these markers and Ki-67, an established strong determinant of metastasis, in estimating progression. Materials/Methods: There were 384 cases in RTOG 92-02 (25.4%) with adequate tissue for immunohistochemical analysis of all three biomarkers (Ki-67, MDM2 and p53). Median follow-up was 96.3 mo. An image analysis system (ChromaVision, San Juan Capistrano, CA) was used to quantify the percentage of tumor nuclei staining positive (PSP) and per sample mean intensity score (MIS) for Ki-67 and MDM2. For p53, the PSP was based on manual counts - image analysis was no better. Cox proportional hazards multivariate analysis (MVA) was used to determine the independence of the biomarkers for local failure (LF), biochemical failure (BF), distant metastasis (DM) and overall mortality (OM). The biomarkers were tested as continuous and dichotomized (Ki-67 <=9% vs >9% n=135; p53 <20% vs >=20% n=92; MDM2 PSP <=40.5% vs >40.5% n=219, median cutpoint and MIS <=167 vs >167 n=204, median cutpoint) variables based on prior analyses. Events were measured from randomization. The other covariates included were dichotomized in accordance with RTOG 92-02 stratification and randomization criteria as follows: median Age (<=70, >70 years), pretreatment PSA (<=30, >30 ng/mL), T-stage (T2c, T3-T4), Gleason score (2-6, 7-10), and assigned treatment (Short Term AD+RT, Long Term AD+RT). Results: There were no statistically significant differences in outcome for those with all biomarker data, versus those with missing data, by any of the endpoints tested. Although all of the covariates mentioned were tested in each MVA, only the results for Ki-67 and MDM2 are shown (Table). p53 was significant only in univariate analysis. As a continuous variable in MVA MDM2 PSP was significantly associated with BF, while MDM2 MIS predicted for BF, DM and OM. As dichotomous variables MDM2 PSP predicted for BF and MDM2 MIS for OM. A composite MDM2 dichotomous covariate of those with PSP >40.5% and MIS >167 (n=159) versus the others, was significantly related to BF, DM and OM. In univariate analysis, the MDM2 composite endpoint of overexpression was associated with a doubling of DM from 10 to 20% and a nearly 10% reduction in survival. Ki-67 was significantly related in MVA to LF, BF and DM when used as a continuous or dichotomous variable. Conclusions: MDM2 overexpression is a robust determinant of BF, DM and OM that is independent of traditional prognostic factors, treatment, p53, and Ki-67, and is a promising therapeutic target.

Choy, H., Swann, S., Curran, W., Whipple, G., Demas, W. and Ettinger, D.: A Phase I Trial of Gemcitabine, Carboplatin or Gemcitabine, Paclitaxel and Concurrent Radiation Therapy Followed by Consolidative Gemcitabine and Carboplatin for Inoperable Stage III Non-Small Cell Lung Cancer: An RTOG 0017 Study. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S42-S43, Abs. #70, 2005. Purpose/Objective: Gemcitabine has been recognized as a potent radiation sensitizer, therefore combining Gemcitabine with radiation in locally advanced non-small cell lung cancer (LANSCLC) is a logical approach to address the need for better local control. The optimal dose of Gemcitabine that can be used with concurrent radiation therapy for LANSCLC has not been well defined, however. Materials/Methods: This phase I trial addresses this question in a two sequence, "ping-pong" trial to find the maximum tolerated dose for gemcitabine administered with carboplatin and thoracic radiation therapy followed by adjuvant chemotherapy (Sequence A) and gemcitabine and paclitaxel administered with thoracic radiation therapy followed by adjuvant chemotherapy (Sequence B). Forty-two patients have been entered in this two two-sequence arm phase I trial. The escalation rule for this trial is that a dose is considered acceptable if, of the first six eligible patients on each arm, fewer than three experience DLTs. A DLT is defined as acute grade 3 or 4 non-hematologic toxicities, grade 4 hematologic toxicities occurring during concurrent chemoradiation therapy; or Grade 3 or 4 pneumonitis or grade 3 or 4 delayed onset esophagitis occurring during the consolidation phase. Results: Sequence B of this two-sequence, "ping-pong" trial closed early due to the toxicity (weekly Gem 300/Paclitaxel 30). On Sequence A, escalation has continued from the initial gemcitabine dose of 300 mg/m2/weekly with no carboplatin (Arm 1) through 3 subsequent escalations: gemcitabine dose of 300 mg/m2/weekly with carboplatin of 2 AUC (Arm 3); gemcitabine of 450 mg/m2/weekly with carboplatin 2 AUC (Arm 5); and the current arm of gemcitabine of 600 mg/m2/weekly with carboplatin 2 AUC (Arm 7). Arm 7 showed 4 DLTs (2 Grade 3 esophagitis; 1 Grade 3 febrile neutropenia; 1 Grade 4 neutropenia). There were two DLTs on Arm 5: 1 Grade 4 leukopenia and 1 Grade 3 esophageal spasm. Therefore the MTD was the Arm 5 dose: 450 mg/m2/wkly of gemcitabine, and 2 AUC carboplatin concurrently with radiation therapy at 1.8 Gy/ 5 days a week, × 5 weeks followed by 2 Gy/ 5 days a week for 9 fractions for a total dose of 63 Gy. Conclusions: A detailed analysis of the fields and volumes of radiation and how they relate to the observed toxicity and efficacy in both sequences will accompany this trial. These data should provide clear direction for the optimal techniques of incorporating gemcitabine in the setting of concurrent radiation.

Bradley, J., Deasy, J., Naqa, I.E., Lindsay, P., Hope, A., Bosch, W., Matthews, J., Sause, W. and Graham, M.: Predictors of Lung Toxicity from the RTOG 9311 Radiation Dose Escalation Trial: GTV Position is Important. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S40-S41, Abs. #67, 2005. Purpose/Objective: We have reported a model for predicting radiation pneumonitis (RP) from our institutional database (ASTRO 2004). Important parameters from that model were sup-to-inf (S-I) GTV position, D35, and max dose. In 9311, the reported rate of >=Grade 3 RP was <=15%. Our aim is to determine the predictors of RP for RTOG 9311 and to test whether our previous model accurately predicted these events. Materials/Methods: Of 179 pts enrolled in RTOG 9311, 10 had unretrievable 3D plans, 31 had <6 mos f/u, and 9 had missing data. 129 were eligible. Toxicity scoring, defined in 9311, was according to RTOG criteria for lung toxicity. 3D plans were processed using CERR. Derived parameters were mean lung dose, GEUD, GTV vol, GTV center position (S-I, A-P, R-L)(scaled 0-1 by maximum lung contour extent), and DVH parameters Dx and Vx, at 5 Gy steps beginning at 5 Gy. Pt-specific parameters included age, sex, KPS, pre-chemo, pre-RT FEV1 and DLCO, and hgb level. A multivariate model was formed by logistic regression of linear combinations of covariables. To maximize the predictive power of our model when extrapolated to another dataset, our strategy consisted of determination of model complexity (number of parameters) and estimation of the most robust model with n parameters. Model order was determined using leave-one-out cross-validation, where all samples but one were used in round-robin testing. Bootstrap samples were queried to determine the best parameters in the n-parameter model. Results: The scatter plot illustrates RP events by maximum dose and V20 for both datasets. The 9311 population differs from our population; higher doses were restricted to lower V20 values. As a result, the model trained on our institutional data was not ideal. The best model (R=0.329, p=0.0001) predicting >=Grade 3 RP in the 9311 dataset included (in order of significance) D15, D30, GTV A-P position (anterior position increases risk), GTV S-I position (inferior position increases risk), and D45. Conclusions: Treatment planning factors predictive for RP differ slightly between RTOG 9311 and our database. This is most likely due to the limited V20s and the higher doses employed on the RTOG trial (i.e. smaller tumors escalated to higher doses). Clinical factors including age, KPS, and PFTs were not predictive. Important predictors of >=Grade 3 RP on RTOG 9311 are Dx parameters D15, D30, and D45 (the minimum doses to the hottest 15%, 30% and 45% of the lung) and GTV position (anterior and inferior GTV positions have hither risk). GTV position, as well as D30 or D35 appear to be important predictors for RP in both data sets.

Machtay, M., Swann, S., Komaki, R., Byhardt, R., Paulus, R., Sause, W., Albain, K.S., Movsas, B. and Curran Jr, W.: Higher BED is Associated with Improved Local-regional Control and Survival for NSCLC Treated with Chemoradiotherapy: An RTOG Analysis. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S40, Abs. #66, 2005. Purpose/Objective: To determine if there is an association between Biologically Equivalent Dose (BED), a measure of radiotherapy dose intensity, and outcomes in patients treated with combined chemotherapy and radiotherapy for locally advanced nonoperative non-small cell lung carcinoma (NSCLC). Materials/Methods: Data were analyzed from six RTOG trials in which concurrent chemoradiotherapy was used for LA NSCLC (RTOG 90-15, 91-06, 92-04, 93-09 nonoperative arm only, 94-10 concurrent arms only, and 98-01). Multiple potential prognostic factors for local-regional control (LRC) and survival were studied, including BED. BED was calculated for each patient using the linear quadratic formula developed by Fowler et al. (Semin Rad Onc 1992; 2:16) and was adjusted for treatment time. The following parameters were used: 1. alpha/beta ratio =10; 2.Effective doubling time (Teff) = 5 days; 3. Kickoff time for accelerated repopulation (Tko) = 14 days. Three different definitions of LRC were studied: 1. Freedom from local progression (FFLP), the traditional RTOG methodology, in which a local-regional failure is intrathoracic tumor progression by WHO criteria; 2. Complete local control (CLC), in which any patient not achieving complete response was considered a local-regional failure at Day 0; and 3. Partial local control (PLC), in which any patient not achieving at least partial response was a local-regional failure at Day 0. Response and progression were based upon institutional reporting; pathologic assessment of intrathoracic control was rarely performed and central review of scans was not performed. Cox and logistic multivariate models tested for associations between LRC and survival and LRC and BED. Results: A total of 1,290 patients were analyzed. LRC was significantly associated with overall survival (p<0.0001). On multivariate analysis, the other significant predictors of overall survival were age (<=70 vs. >70), Karnofsky Performance Status (90/100 vs. 70/80), histology (non-squamous was better than squamous), and BED. For every increase of 10 Gy BED, there was an 18% decrease in the risk of death (p<0.0001). The LRC rates differed based upon the definition of LRC that was employed. The 5-year actuarial rate of FFLP was 30%; the 5-year rate of PLC was 7%; and the 5-year rate of CLC was 3%. Radiotherapy dose intensity using the BED model was associated with LRC using the FFLP and PLC definitions but not the CLC definition. The odds ratio for local-regional failure was 0.77 for an increase of 10 Gy BED using the FFLP definition (p<0.0001). The odds ratio for local-regional failure was 0.64 for an increase of 10 Gy BED using the PLC definition (p=0.0005). BED was not significantly associated with CLC (odds ratio = 0.84, p = 0.1385). Conclusions: LRC is suboptimal after chemoradiotherapy as delivered in the RTOG experience. Increased radiotherapy dose intensity as defined by the (time-adjusted) BED model is associated with improved survival and LRC (as defined by FFLP and/or PLC, above). Further exploration of radiotherapy dose intensity is indicated.

Lawton, C., DeSilvio, M., Roach III, M., Uhl, V., Krisch, R., Seider, M., Rotman, M., Jones, C., Asbell, S., Valicenti, R., Han, S. and Thomas, C.: 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. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S19, Abs. #32, 2005. Purpose/Objective: This trial was designed to test the hypothesis that TAS and WP radiotherapy (RT) followed by a prostate boost improves the progression-free survival (PFS) by at least 10% compared to TAS and PO RT. This trial was also designed to test the hypothesis that neoadjuvant hormonal therapy(NHT) followed by concurrent TAS and RT improves the PFS compared to RT followed by adjuvant TAS (AHT) by at least 10%. Materials/Methods: Patients eligible for the study included those with clinically localized adenocarcinoma of the prostate and an elevated prostate specific androgen (PSA) < 100ng/ml. Patients were stratified by T stage, PSA, and Gleason score (GS) and required to have an estimated risk of lymph node (LN) involvement > 15% based on the equation +LN = (2/3) PSA + (GS-6) × 10. TAS consisted of an LHRH agonist (Leuprolide or Goserelin) and Flutamide 250 mg p.o. tid administered two months before and during RT (NHT) or for four months following the completion of RT (AHT). Accrual of 1,323 cases occurred between April 1, 1995 and June 1, 1999. Three hundred and thirty two, 331, 329, and 331men were randomized to WP RT + NHT, PO RT + NHT, WP RT + AHT, and PO RT + AHT respectively. 73% of patients had a Gleason score > 7, median PSA was 23ng/ml and 67% of patients had > T2c disease. The study design resulted in a balance between all four arms for clinical stage, GS, PSA, and estimated risk of lymph node involvement. PSA failure was defined as two consecutive rises or a PSA > 4ng/ml at the last follow up after the PSA nadir value was reached. Results: With a median follow up since study entry for all patients of 5.9 years, patients treated with WP RT + NHT in pair wise comparison analysis show a statistically significant difference in PFS over PO RT +NHT (p=0.0041) and a statistically significant improvement over WP RT + AHT (p=0.0045). WP RT + NHT shows a trend in progression free survival over PO RT + AHT (p= 0.0656). Five year PFS for WP RT + NHT, PO RT + NHT, WP RT + AHT and PO RT + AHT is 48.3%, 36.8%, 38.1%, and 40.4% respectively. Biochemical failure was also statistically significantly improved in pair wise comparison analysis for WP RT + NHT versus PO RT + NHT (p=0.0070), WP RT + NHT versus WP RT + AHT shows a trend towards significance with a (p=0.0699). WP RT + NHT versus PO RT + AHT was not statistically different regarding protocol definition of biochemical failure (p=0.2181). The five year biochemical failure rate for WP RT + NHT, PO RT + NHT, WP RT + AHT, and PO RT + AHT were 35.9%, 45.5%, 42.8%, and 40.0% respectively. To date no overall survival advantage has been seen. At five years overall survival for WP RT + NHT, PO RT + NHT, WP RT + AHT, and PO RT + AHT are 81.6%, 77.8%, 75.5%, and 81.2% respectively. Conclusions: This updated analysis reveals that WP RT + NHT is associated with improved PFS over PO RT + NHT and WP RT + AHT and trends toward improved PFS over PO RT + AHT. WP RT + NHT is associated with improved biochemical failure over PO RT + NHT, marginal improvement over WP RT + AHT, but may not be different from PO RT + AHT. Longer follow up is needed to confirm the benefit of these findings in regards to overall and cause specific survival.

Swanson, G., Thompson, I., Tangen, C., Miller, G., Lucia, M.S., Troyer, D., Paradelo, J., Chin, J., Messing, E., Canby-Hagino, E., Forman, J. and Crawford, E.D.: Phase III Randomized Study of Adjuvant Radiation Therapy versus Observation in Patients with Pathologic T3 Prostate Cancer (SWOG 8794). Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S1, Abs. #1, 2005. Purpose/Objective: Southwest Oncology Group Protocol 8794 was a randomized study to determine whether patients with pathologic T3 prostate cancer benefited from immediate adjuvant radiation therapy. Materials/Methods: From 1988-1995, 473 patients with pathologically determined extracapsular extension, positive margins and/or seminal vesicle involvement were randomized to radiation (60-64 Gy) versus observation. Follow up with PSA was every three months in year one, every 6 months for years 2-3 and annually thereafter. Patients were followed until death. The primary endpoint was metastasis free survival. Results: Four hundred ten patients were eligible for follow up. Median follow up was 9.7 years. Biochemical free survival (PSA <0.4 ng/ml) was significantly improved with radiation, while metastatic free survival and overall survival were non-significantly improved (table). The benefit for radiation was seen in each of the three pathologic risk groups. For patients with seminal vesicle involvement, with radiation (22 patients) 5 year bDFS was 57% and without radiation (21 patients), 22%. In the observation group, 32% subsequently received radiation. Of the 213 radiation patients, 84 (39%) subsequently were treated with androgen ablation at a median of 12.4 years and in the initial observation group, 106/210 (50%) subsequently received androgen ablation at a median of 9.9 years. At 6 weeks (during radiation), both GI and GU toxicity were significantly worse in the radiation arm. By two years, there was no significant difference in quality of life between the two groups.

Conclusions: Conclusions: Adjuvant radiation for pT3 disease significantly improved 5 and 10 year biochemical disease free survival and none significantly improved metastasis free and overall survival. Radiation prevented the need for androgen ablation in some patients and delayed the use by 2.5 years in the rest. Long term quality of life was not adversely affected by radiation therapy. Pathological T3 patients should be given the opportunity to receive post operative radiation.

Young, B., Swann, S., Berkey, B., Motyka-Welsh, E., Caldwell, T. and King, S.: Enhancing the Organizational Efficiency of The Radiation Therapy Oncology Group Through a Continuous Quality Improvement Initiative. Proc Amer Soc Thera Rad Onc (ASTRO), Denver, CO, Int J Radiat Oncol Biol Phys, [63] (Suppl. 1), pg. S385-S386, Abs. #2266, 2005. Purpose/Objective: Leadership of the Radiation Therapy Oncology Group and the American College of Radiology recognized the need, in the face of flat National Cancer Institute funding levels, to enhance the productivity and efficiency of decades-old processes and systems within the RTOG Headquarters. Materials/Methods: Thus began a continuous quality improvement initiative within the ACR offices of RTOG Headquarters. The process-oriented transition began on a number of parallel tracks. Fundamental processes in clinical trial development and execution were evaluated and improved. Structural changes in the functional silos of statistics, data management, radiation therapy quality assurance, and protocol development were made. The management of the Group's significant data load was examined and the data management paradigm transformed. Results: The RTOG has, through these efforts, further enhanced its performance in the competitive realm of cooperative clinical trials groups. Conclusions: Continuous quality improvement initiatives enhance performance of the RTOG cooperative clinical trials group.