2005 ASCO Booklet [PDF]

Reference	Study Number
Kaufman, D., Winter, K., Shipley, W., Althausen, A., Hug, E., Toonkel, L. and H, S.: Muscle-Invading Bladder Cancer, RTOG Protocol 99-06: Initial Report of a Phase I/II trial of Selective Bladder-Conservation Employing TURBT, Accelerated Irrdiation Sensitized with Cisplatin and Paclitaxel Followed by Adjuvant Cisplatin and Gemcitabine Chemotherapy. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 379s, Abs. #4506, 2005.	9906 (acc as oral pres)
Cardinale, R. M., Won, M., Choucair, A., Gillin, M., Chakravarti, A., Schultz, C., Souhami, L., Chen, A., Pham, H. T. and Mehta, M.: A Phase II Trial of Accelerated Radiotherapy Using Weekly Stereotactic Conformal Boosts for Supratentorial Glioblastoma Multiforme. RTOG-0023. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23S] (16S) pg. 116s, Abs. #1511, 2005.	0023 (acc as poster disc)
Knisely, J., Berkey, B., Chakravarti, A., Yung, W. A., Curran, W., Robins, H. I., Movsas, B., Brachman, D., Henderson, R. and Mehta, M.: RTOG 0118: A Phase III Study of Conventional Radiation Therapy Alone vs. Conventional Radiation Therapy Plus Thalidomide for Multiple Brain Metastases. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 114s, Abs. #1500, 2005.	0118 (acc as oral pres)
Vogelbaum, M., Berkey, B., Peereboom, D., Giannini, C., Suh, J., Brown, P. D., Blumenthal, D., Biggs, C., Schultz, C. and Mehta, M.: RTOG 0131: Phase II Trial of Pre-Irradiation and Concurrent Temozolomide in Patients with Newly Diagnosed Anaplastic Oligodendrogliomas and Mixed Anaplastic Oligodendrogliomas. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 119s, Abs. #1520, 2005.	0131 (acc as poster disc)
Horwitz, E., Harris, J., Langer, C., Nicolaou, N., Kies, M., Curran Jr, W., Wong, S. and Ang, K. K.: Concurrent Split Course Hyperfractionated Radiotherapy (Hfx RT), Cisplatin (DDP) and Paclitaxel (P) in Patients with Recurrent, Previously Irradiated Squamous Cell Carcinoma of the Head and Neck (SCCHN): Update of RTOG 9911. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 519s, Abs. #5577, 2005.	9911 (acc as gen poster)
Hartsell, W., Winter, K., Watkins-Bruner, D., Scarantino, C., Ivker, R., Roach III, M., Suh, J., Demas, W., Movsas, B., Petersen, I. and Konski, A.: Breast Cancer Patients Have Better Outcomes than Prostate Cancer Patients for Palliation of Painful Bone Metastases: Results of RTOG 97-14. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 546s, Abs. #6073, 2005.	9714 (acc as gen poster)
Valicenti, R., DeSilvio, M., Hanks, G., Porter, A., Brereton, H., Shipley, W. and Sandler, H.: Surrogate Endpoint for Prostate Cancer-specific Survival: Validation from an Analysis of Radiation Therapy Oncology Group Protocol 92-02. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 390s, Abs. #4549, 2005.	9202 (acc as poster disc)
Okawara, G., Winter, K., Donohue, J., Pisters, P., Crane, C., Greskovich, J., Anne, P. R., Bradley, J., Willet, C. and Ajani, J.: A Phase II Trial of Preoperative Chemotherapy and Chemoradiotherapy for Potentially Resectable Adenocarcinoma of the Stomach (RTOG 99-04). Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 312s, Abs. #4019, 2005.	9904 (acc as poster disc)
Schwartz, G., Winter, K., Minsky, B., Janjan, N., Schaefer, P., Thomson, J., Anne, P. R., Gross, H., Willet, C. and Kelsen, D.: A Randomized Phase II Trial Comparing Two Paclitaxel (P)-Cisplatin (C) Containing Chemoradiation (CRT) Regimens as Adjuvant Therapy in Resected Gastric Cancer (RTOG Intergroup #0114). Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 312s, Abs. #4020, 2005.	0114 (acc as poster disc)
Torres-Roca, J., DeSilvio, M., Mora-Diaz, L., Hammond, E., Ahmad, N., Jove, R., Forman, J., Lee, R., Sandler, H. and Pollack, A.: Stat3 as a Correlate of Distant Metastasis in RTOG 86-10. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 416s, Abs. #4656, 2005.	8610 (acc for publication, not presentation)
Trotti, A., Pajak, T., Gwede, C., Paulus, R., Cooper, J., Forastiere, A., Garden, A. and Ang, K. K.: The TAME Adverse Event Summary and Risk Classification System:Analysis of the RTOG H&N Database. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 534s, Abs. #6026, 2005.	9003, 9111, 9501, 9703, 9914 (acc as poster disc) C. Earle, MD will present this abs. at the meeting.
Werner-Wasik, M., Swann, S., Curran Jr, W., Robert, F., Komaki, R., 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 Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 654s, Abs. #7135, 2005.	324 (acc as gen poster)
Bradley, J., Graham, M., Swann, S., Byhardt, R., Govindan, R., Fowler, J., Purdy, J., Michalski, J., Gore, E. and Choy, H.: Phase I Results of RTOG L-0117; A Phase I/II Dose Intensification Study Using 3DCRT and Concurrent Chemotherapy for Patients with Inoperable NSCLC. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 636s, Abs. #7063, 2005.	117 (acc as poster disc)
Swann, S., Machtay, M., Komaki, R., Langer, C., Sause, W., Langer, C., Byhardt, R. and Curran Jr, W.: Impact of Overall Treatment Time During Concurrent Chemoradiotherapy for Locally Advanced NSCLC: An RTOG Secondary Analysis. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 635s, Abs. #7061, 2005.	9106, 9204, 9410 (acc as poster disc)
Albain, K. S., Swann, S., Rusch, V., Turrisi, A. T., Shepherd, F., Smith, C., Gandara, D., Johnson, D., Green, M. and Miller, R.: Phase III Study Of Concurrent Chemotherapy And Radiotherapy (CT/RT) Vs CT/RT Followed By Surgical Resection For Stage IIIA(Pn2) Non-Small Cell Lung Cancer (NSCLC): Outcomes Update Of North American Intergroup 0139 (RTOG 9309). Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 624s, Abs. #7014, 2005.	9309 (acc as oral pres)
Choy, H., Swann, S., Walter, C., 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 Study. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 646s, Abs. #7103, 2005.	0017 (acc as gen poster)
Kumar, P., Robbins, K. T., Harris, J., McCulloch, T., Cmelak, A., Sofferman, R., Levine, P. and Fu, K.: Mature Results of Radiation Therapy Oncology Group (RTOG) Trial 9615 Using Intra-Arterial Cisplatin (IA-P) and Concurrent Radiation Therapy (RT) for Stage IV-T4 Head/Neck (H/N) Squamous Cell Carcinoma (SCCa). Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 519s, Abs. #5579, 2005.	9615 (acc as gen poster)

NCI Sponsored Trials
Soares, H., Kumar, A., Serdarevic, F., Fiorica, J., Wells, R., Swann, S., Buckner, J., Sargent, D., Hozo, I. and Djulbegovic, B.: Equipoise Principle and NCI-Sponsored Clinical Trials: Are Investigators Truly Uncertain About Their Comparisons? Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 540s, Abs. #6050, 2005.	(acc as gen poster)
Djulbegovic, B., Kumar, A., Soares, H., Serdarevic, F., Wells, R., Fiorica, J., Swann, S., Buckner, J., Sargent, D. and Hozo, I.: A Relationship Between Ethics of Clinical Trials and Therapeutic Advances in Cancer. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 550s, Abs. #6090, 2005.	(acc for publication only)
Kumar, A., Soares, H., Serdarevic, F., Hozo, I., Buckner, J., Wells, R., Fiorica, J., Swann, S., Sargent, D. and Djulbegovic, B.: How Many New Treatments are "Breakthroughs"? Evaluation of Innovations in Cancer. Proc Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, [23] (16S) pg. 544s, Abs. #6066, 2005.	(acc as gen poster)

K. S. Albain, S. Swann, V. Rusch, A. T. Turrisi, F. Shepherd, C. Smith, D. Gandara, D. Johnson, M. Green and R. Miller: Phase III Study Of Concurrent Chemotherapy And Radiotherapy (CT/RT) Vs CT/RT Followed By Surgical Resection For Stage IIIA(Pn2) Non-Small Cell Lung Cancer (NSCLC): Outcomes Update Of North American Intergroup 0139 (RTOG 9309). Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):624s, 2005. Background: Surgery after CT/RT remains controversial for patients (pts) with stage IIIA(pN2) NSCLC. Initial analyses of INT 0139 showed significantly better progression-free survival (PFS), but not overall survival (OS), in the trimodality arm. (PASCO 2003) With longer follow-up (>=2.5 yrs per pt), new analyses of primary endpoints PFS and OS were conducted. Methods: Pts with PS 0-1 and T1-3, pN2, M0 NSCLC were randomized if resection was technically feasible. All received cisplatin 50 mg/m2 d1, 8, 29, 36 and etoposide 50 mg/m2 d1-5, d29-33 (PE) and RT to 45 Gy starting day 1. Arm 1 had resection if no progression (PD), then PE X2; Arm 2 completed RT to 61 Gy with PE X2. Intent to treat analyses used Kaplan-Meier estimates, log-rank tests and Cox multivariate models; exploratory analyses used logistic regression. All CI are 95% and p-values, 2-sided. Results: 396 eligible pts were enrolled (Arm 1, 202; Arm 2, 194; well-balanced on all factors). Treatment-related deaths: Arm 1, 16 (7.9%), of which 10 (5.0%) were within 30 days postop; Arm 2, 4 (2.1%). Deaths by type of surgery: 5/23 (22%) simple and 9/31 (29%) complex pneumonectomies, 1/98 (1%) lobectomies. Arm 1 pathology (n=164): T0N0, 29 (18%); TanyN0, 76 (46%). Arm 1 PFS is superior: median 12.8 vs 10.5 mos, p=0.017, HR 0.77 (0.62, 0.96); 5-yr 22.4% vs 11.1%. More pts on Arm 1 are alive without PD (p=0.008), but more died without PD (p=0.021). OS curves overlap for 2 yrs, but separate late favoring Arm 1: median 23.6 vs 22.2 mos, p=0.24, HR 0.87 (0.70,1.10); 5-yr 27.2% vs 20.3%, odds ratio for 5-yr survival 0.63 (0.36, 1.10, p=0.10). 96 pts are alive/censored. Independent favorable OS predictors: female, no weight loss. Arm 1 5-yr OS if pN0 at surgery was 41%; pN1-3, 24%; no surgery, 8% (p< 0.0001). Conclusions: 1) Longer follow-up of INT 0139 confirms significantly improved PFS but not OS when surgery follows CT/RT in pts with stage IIIA(pN2) NSCLC, 2) there is a trend for better 5-yr OS with trimodality therapy, 3) pN0 at surgery predicts long-term survival, 4) surgery after CT/RT can be considered in fit pts, 4) this approach may not be optimal if a pneumonectomy is needed.

J. Bradley, M. Graham, S. Swann, R. Byhardt, R. Govindan, J. Fowler, J. Purdy, J. Michalski, E. Gore and H. Choy: Phase I Results of RTOG L-0117; A Phase I/II Dose Intensification Study Using 3DCRT and Concurrent Chemotherapy for Patients with Inoperable NSCLC. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):636s, 2005. Background: The standard radiation dose for NSCLC was established by RTOG 7301 as 60 Gy. Local failure rates with this dose remain unacceptably high. Current cooperative group trials continue to use doses of 60-63 Gy in the setting of concurrent chemotherapy. The primary endpoint of the Phase I portion was to establish the maximum tolerated dose (MTD) of radiation therapy, in the setting of concurrent chemotherapy, using 3DCRT for NSCLC. Methods: Eligibility included patients with histologically proven, unresectable Stages I-III NSCLC and a Zubrod perfomance status of 0-1. Weight loss eligibility was <=10%. Concurrent chemotherapy consisted of paclitaxel 50 mg/m2 and carboplatin AUC=2 given weekly. Radiation dose was to be sequentially intensified by increasing the daily fraction size starting at 75.25 Gy/35 fractions. Interim analysis was planned after the initial 7 patients were enrolled with application of the stopping rule if DLTs occurred in 2 or more patients. Radiation therapy volumes consisted of gross tumor and nodes plus a margin. Elective lymph nodes were not included in the treatment fields. Technical criteria included strict dosimetric constraints on the normal lung (V20 <=30%) and esophagus (mean dose <3=4 Gy and V55 <= 30%) and water-based dose calculations prescribed to the isocenter. Results: The Phase I portion of this study accrued 17 patients from 10 institutions and was closed in January 2004. After the initial eight patients were accrued to Arm 1, the trial closed temporarily on September 26, 2002 due to reported toxicity. Two acute treatment-related DLTs were reported: a grade 5 and a grade 3 pneumonitis. Subsequent DLTs since closure of Arm 1 include a grade 3 late pneumonitis and a grade 4 pain toxicity. The protocol was revised to de-escalate the radiotherapy dose (74 Gy/37 fractions). Arm 2 accrued 9 patients. One patient on Arm 2 developed a grade 3 esophagitis. Conclusions: The MTD was determined to be 74 Gy/37 fractions (2.0 Gy per fraction) using 3DCRT with concurrent paclitaxel and carboplatin. The Phase II component of RTOG L-0117 remains open to accrual at 74 Gy.

R. M. Cardinale, M. Won, A. Choucair, M. Gillin, A. Chakravarti, C. Schultz, L. Souhami, A. Chen, H. T. Pham and M. Mehta: A Phase II Trial of Accelerated Radiotherapy Using Weekly Stereotactic Conformal Boosts for Supratentorial Glioblastoma Multiforme. RTOG-0023. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23S] (16S):116s, 2005. Background: Malignant gliomas undergo molecular changes during radiation therapy (RT) that lead to accelerated proliferation. This phase II trial was performed to assess the feasibility, toxicity, and efficacy of dose-intense RT employing weekly fractionated stereotactic radiotherapy (FSRT) boosts for patients with glioblastoma multiforme (GBM). Methods: Patients with histologically confirmed GBM with postoperative enhancing tumor plus tumor cavity diameter <= 60 mm were enrolled. 50 Gy of standard RT was given in daily 2 Gy fractions. In addition, patients received four FSRT treatments, once weekly, during weeks 3-6 in lieu of standard RT to the postoperative tumor bed plus enhancing tumor plus 5 mm (PTV). FSRT dosing of either 7 Gy (PTV<=40 mm) or 5 Gy (PTV>40 mm) per fraction was given for a cumulative dose of 70 or 78 Gy in 29 (25 standard RT + 4 FSRT) treatments over 6 weeks. A relocatable frame and shaped conformal fields were used for FSRT. Following the RT course, BCNU at 80 mg/m2 was given for 3 days, q 8 weeks, for 6 cycles. The sample size was calculated to compare survival with RTOG-RPA class using one-sided p-values and calculated hazard ratios. Results: 76 patients were analyzed. Significant RT toxicity included: one grade 4 acute (lethargy) and one grade 3 late (necrosis). The median survival time (MST) was 12.5 months. No survival difference is seen compared to the RTOG historical database. Matched pair cox regression also showed no significant survival difference. For RPA class IV patients (50% of total) the MST was 14.7 mos. compared to 11.3 mos. for historic controls (p=0.15). Patients with gross total resection (41%) had a MST of 16.1 mos. vs. 12.0 mos. for historic controls (p=0.19). RT quality control was favorable with 90% compliance. Conclusion: This initial RTOG trial employing FSRT was feasible and well tolerated. There appears to be no significant survival benefit for GBM patients using this dose-intense, accelerated RT regimen although RPA class IV and gross total resection patients trended toward improved outcome.

H. Choy, S. Swann, C. Walter, G. Whipple, W. Demas and D. Ettinger: 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 Study. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):646s, 2005. Background: Gemcitabine has been recognized as a potent radiation sensitizer, therefore combining Gemcitabine (Gem) with thoracic radiation therapy(TRT) 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 Gem that can be used with concurrent TRT for LANSCLC has not been well defined. Methods: This phase I trial addresses this question in a two sequence (Seq), "ping-pong" trial to find the maximum tolerated dose for Gem administered with carboplatin(Carbo) and TRT followed by adjuvant chemotherapy (Seq A) and Gem and paclitaxel administered with TRT followed by adjuvant chemotherapy (Seq B). Results: Thirty-five patients have been entered as of 12/04. The escalation rule is that a dose is considered acceptable if, of the first 6 eligible patients on each arm, fewer than 3 experience DLTs. A DLT is defined as acute grade 3/4 non-hem toxicities, grade 4 hem toxicities occurring during concurrent Chemo/TRT; or Grade 3/4 pneumonitis or grade 3/4 delayed onset esophagitis occurring during the consolidation phase. Seq B of this two-seq, "ping-pong" trial closed on 5/22/2003 because of excessive toxicity . On Seq A, escalation has continued from the Arm 1 through 7. MTD has not been reached in seq A as of Arm 5. The study is currently on hold for toxicity assessment of Arm 7. If Arm 7 has fewer than 3 DLTs, study will be re-open at Arm 9 (Gem dose of 750mg/m2/weekly with carbo of 2 AUC). More mature data will be available after patient accrual and toxicity assessments are completed. Conclusions: A detailed analysis of the fields and volumes of TRT and how they relate to the toxicity and efficacy will be presented. These data should provide clear direction for the optimal techniques of incorporating gemcitabine in the setting of concurrent TRT. Sequence A       Sequence B     Gemcitabine Carboplatin # of patients   Gemcitabine Paclitaxel # of patients Level (mg/m2/wkly) (AUC)   Level (mg/m2/wkly) (mg/m2/wkly)   Arm 1 300 0 7 Arm 2 300 20 8 Arm 3 300 2 6 Arm 4 450 20 0 Arm 5 450 2 7 Arm 6 450 30 0 Arm 7 600 2 7 Arm 8 600 30 0 Arm 9 750 2 0 Arm 10 600 40 0 Arm 11 900 2 0 Arm 12 750 40 0

B. Djulbegovic, A. Kumar, H. Soares, F. Serdarevic, R. Wells, J. Fiorica, S. Swann, J. Buckner, D. Sargent and I. Hozo: A Relationship Between Ethics of Clinical Trials and Therapeutic Advances in Cancer. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):550s, 2005. Background: We hypothesized that there is a predictable relationship between equipoise and the outcomes of trials, i.e. the equipoise principle bounds therapeutic advances in a such way that, over time, distribution of successes between experimental and standard treatments is expected to be about equal, reflecting the unpredictability of treatment success for a particular intervention. We tested this hypothesis in randomized controlled trials (RCT) performed by the National Cancer Institute (NCI) sponsored Cooperative Groups (CG), systematically taking into account all factors (publication bias, methodological quality, choice of control intervention) known to affect outcomes. Methods: All completed (published and unpublished) phase 3 RCTs from 6 CGs (563 trials, ~ 149,000 patients) since 1955 were evaluated. Success of experimental vs. standard treatments was evaluated semi-quantitatively and quantitatively using a meta-analytic technique. Results: Investigator's preference for experimental vs. standard treatments were 43% and 57%, respectively (p=0.002). Hazard ratio for overall survival was 0.96 [99% CI (0.95, 0.98), p=0.00001] and for event-free survival was 0.92, [99%CI (0.90, 0.93), p=0.0001] slightly favoring experimental treatments but at the expense of increased treatment-related mortality [HR 1.12, 99%CI (1.01, 1.25), p=0.04]. The results adhere to the equipoise hypothesis and were not affected by any factors known to bias outcomes. Conclusions: While many successful treatments are discovered in phase 3 RCTs, innovative treatments in cancer which have progressed to testing in RCTs are, on average, as likely to be inferior or superior to standard treatments. This result was predicted, which amounts to description of the law of therapeutic advances in clinical oncology. If the distribution of the results were significantly skewed to consistently and predictably favor one type of treatments over another, the clinical trial system would come to a halt (patients would naturally request only those treatments that are expected to be superior making randomization impossible). Progress in treating cancer is ultimately determined by the ethical principle of equipoise which should guide clinical research.

W. Hartsell, K. Winter, D. Watkins-Bruner, C. Scarantino, R. Ivker, M. Roach III, J. Suh, W. Demas, B. Movsas, I. Petersen and A. Konski: Breast Cancer Patients Have Better Outcomes than Prostate Cancer Patients for Palliation of Painful Bone Metastases: Results of RTOG 97-14. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):546s, 2005. Background: It is unclear whether there are gender-based differences in pain response and survival after palliative external beam radiotherapy (XRT) for painful bone metastases from breast or prostate cancers. Methods: RTOG and NCCTG conducted a randomized, prospective phase III study of XRT for patients with breast or prostate cancer and painful bone metastases (Brief Pain Index (BPI) worst pain score of >=5 out of 10). Patients were randomized to 8 Gy in a single fraction vs. 30 Gy in 10 fractions, stratified by number of painful sites, weight bearing site, worst pain score and bisphosphonate usage. Results of the primary study are reported elsewhere; XRT was very effective, providing pain relief in 66% of patients. At 3 months follow-up, there was no difference between the two treatment arms, regardless of stratification. Results: In this gender-based analysis, there were 453 women with breast cancer and 445 men with prostate cancer; median age was 58 and 71 years, respectively. Stratification variables were balanced other than more women received bisphosphonates (46% vs 8% of men). Pain relief was evaluated at 3 months using the BPI. For breast and prostate cancer, complete response was seen in 17% and 16% and partial response in 54% and 43% for an overall response rate of 71% and 59% (p=0.0034) Median survival on the 30 Gy arm for women was 11.6 months compared to 7.3 months for men and median survival on the 8 Gy arm for women was 12.5 months compared to 7.9 months for men. Separate multivariate analyses of the 30 Gy arm and 8 Gy arm, showed that women with breast cancer had statistically significantly longer survival compared to men with prostate cancer (30Gy: HR 1.78, p-value <0.0001; 8Gy: HR 1.75, p-value < 0.0001), after adjusting for age (which was not significant) and KPS. Conclusions: Women with bone metastases from breast cancer experience better outcomes in terms of pain control and survival compared to men with prostate cancer with bone mets treated with palliative radiotherapy. Further consideration should be given to tailoring treatment by gender. Acknowledgment: This trial was supported by NCI grants RTOG U10 CA21661, CCOP U10 CA37422, and Stat U10 CA32115.

E. Horwitz, J. Harris, C. Langer, N. Nicolaou, M. Kies, W. Curran Jr, S. Wong and K. K. Ang: Concurrent Split Course Hyperfractionated Radiotherapy (Hfx RT), Cisplatin (DDP) and Paclitaxel (P) in Patients with Recurrent, Previously Irradiated Squamous Cell Carcinoma of the Head and Neck (SCCHN): Update of RTOG 9911. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):519s, 2005. Background: Chemotherapy (CTx) alone (eg. DDP, 5FU) remains the standard therapy for recurrent SCCHN, but yields median survival times (MST) of only 8-10 mos & 1 yr survival (OS) of <= 35% at best. For limited relapse or new unresectable SCCHN within previous RT portals, a potential role for re-irradiation combined with radiosensitizing CTx, exists. Based on a prior phase I trial of split course HFx RT/ DDP/ P, in which we observed a response rate of 55% & >= 2 yr progression-free survival (PFS) in 5 of 31 pts (ASCO 1999, A-1551), RTOG initiated a phase II trial. Methods: Eligibility stipulated recurrent SCCHN or second 1° tumors (SPT) in a previous RT field with >= 75% of tumor volume previously treated to 45 Gy-75 Gy; >= 6 mos elapsed from prior RT, ECOG PS 0-1; ANC >=1500, plts ? 100K, bili <=1.5 mg/dl, creat <= 1.5 mg/dl, & absence of distant mets. Pts received HFx RT (1.5 Gy/Fx BID x 5d every 2 wks x 4), in combination with DDP 15 mg/m2 IV QD x 5 & P 20 mg/m2 IV QD x 5 q 2 wks x 4. G-CSF was given days 6 through 13 of each 2 wk cycle. Results: 105 pts (median age 60; 77% male; 66% PS 1) were entered between 3/00 & 6/03; 99 proved eligible. 23% had SPTs. Oropharynx (40%) & oral cavity (27%) were the predominant 1° sites. Median prior RT dose was 65.4 Gy (range, 45-75 Gy), median time from prior RT 40 mos. 74% of pts received all 4 scheduled cycles of chemo; 69% received RT as planned (median dose 60 Gy). Gr >= 4 acute toxicity (tox) occurred in 28%, gr >= 3 leukopenia in 30%, gr >= 3 anemia in 21%, and gr >= 3 GI toxicity in 48%. Delayed osteoradionecrosis occurred in 4%. There were 8 fatal (Gr 5) toxicities: 5 in the acute period (dehydration, pneumonitis, neutropenic fever [2], CVA) & 3 late (carotid hemorrhage in 2). At a median follow-up of 23.6 mos, MST is 12.1 mos with est. 1- & 2-yr OS rates of 50.2% (95% CI: 40.0, 59.6) & 25.9% (17.3, 35.3). Median & 1-yr PFS are 7.8 mos & 35% (CI 25.7, 44.4) Conclusions: Despite a fairly high incidence of Gr 5 tox, the 1- & 2-yr OS rates for split course HFxRT/DDP/P exceed results generally seen with chemotherapy alone. A phase III trial directly comparing CTx alone to concurrent CTx & re-irradiation with survival as the 1° enpoint is planned.

D. Kaufman, K. Winter, W. Shipley, A. Althausen, E. Hug, L. Toonkel and S. H: Muscle-Invading Bladder Cancer, RTOG Protocol 99-06: Initial Report of a Phase I/II trial of Selective Bladder-Conservation Employing TURBT, Accelerated Irrdiation Sensitized with Cisplatin and Paclitaxel Followed by Adjuvant Cisplatin and Gemcitabine Chemotherapy. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):379s, 2005. Background: To examine the protocol completion and response rate of cisplatin plus paclitaxel and twice-daily irradiation following TURBT to preserve the bladder and to determine the tolerance of 4 cycles of chemotherapy. Methods: Induction treatment involved 13 days of twice-daily irradiation, cisplatin (20 mg/m2) on the first two days of each week, and paclitaxel (50 mg/m2) on the first day of each week. Three weeks following induction, patients were cystoscopically evaluated for residual disease. Those whose tumor-site biopsies showed no disease completed consolidation chemoradiation. Patients with residual tumor went on to cystectomy. Following consolidation or cystectomy patients were to complete 4 cycles of cisplatin and gemcitabine chemotherapy. Results: Fifty patients, staged T2-T4a N0 M0 were entered onto the treatment regimen. Forty-seven patients were evaluable for the primary endpoint of treatment completion. Clinical T-stages were: T2 (90%), T3a (8%) and T3b (2%). Median followup was 30 months. Thirty-four (72%) of the 47 evaluable patients completed all treatment per protocol or with an acceptable variation. The complete response (CR) rate after induction therapy was 87%. Grade 3 or 4 toxicity was observed in 32% of patients (induction and consolidation), and in 74% during adjuvant chemotherapy. Twenty-nine percent experienced Grade 4 toxicities during followup, mainly hematologic, and one Grade 5. Conclusions: Although we did not achieve a 90% protocol completion rate with this treatment regimen, it did result in a CR rate of 87%. These early outcomes are encouraging in that this protocol regimen, the first to include adjuvant treatment with cisplatin and gemcitabine may be effective in cancer control. This trial was supported by NCI U10 CA21661 and Eli Lilly & Co. Endpoints for 49 Patients # Failures 12 Month EstimatedRates 24 Month Estimated Rates Local Failure Following Post Induction CR (n=37) 7 (4 non-invasive) 13% 18% Regional Nodal Failure 4 6% 6% Distant Metastases Failure 11 10% 17% Overall Survival 12 88% 79% Surviving with Bladder Intact 15 80% 69%

J. Knisely, B. Berkey, A. Chakravarti, W. A. Yung, W. Curran, H. I. Robins, B. Movsas, D. Brachman, R. Henderson and M. Mehta: RTOG 0118: A Phase III Study of Conventional Radiation Therapy Alone vs. Conventional Radiation Therapy Plus Thalidomide for Multiple Brain Metastases. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):114s, 2005. Background: Thalidomide was selected by the RTOG for evaluation in combination with cranial irradiation (WBRT) for brain metastases because of its potent antiangiogenic and immunomodulatory activity. Methods: Patients with multiple brain metastases or metastases not eligible for radiosurgery due to size or location and Zubrod 0-1 were enrolled and stratified by RPA class and whether chemotherapy was planned after WBRT. Arm 1 patients were treated with 15 fractions of WBRT (2.5 Gray per fraction, 37.5 Gy total dose; arm 2 patients received the same WBRT and oral thalidomide). Thalidomide was started with WBRT at 200 mg po qhs and escalated as tolerated. The study was designed to enroll 332 patients and have an 80% power to detect a 35% increase in median survival with an overall Type I error of 0.05, using a one sided log-rank test. Early stopping guidelines were to be invoked if either the log-rank test's p value was <0.0077 in favor of thalidomide or if the conditional, statistical power of detecting the hypothesized benefit was less than 15%. Results: At the time of the pre-planned blinded analysis, 168 patients were enrolled and 149 were analyzed. There were 87 deaths reported at that time. Follow-up was 0.3-15.9 months (median 2.4 months). Median survivals for arm 1 and 2 were 3.6 and 4.4 months. Arm 1 had 3 deaths and arm 2 had 2 deaths from causes known to be possible thalidomide toxicities. The one sided log-rank test's p value was 0.44, and the conditional power was <1%. It was concluded that observing a treatment difference was very unlikely, and the study was closed to new patient entries. Conclusions: Thalidomide does not improve survival in patients receiving WBRT for multiple brain metastases. This trial was supported by the NCI & Celgene.

A. Kumar, H. Soares, F. Serdarevic, I. Hozo, J. Buckner, R. Wells, J. Fiorica, S. Swann, D. Sargent and B. Djulbegovic: How Many New Treatments are "Breakthroughs"? Evaluation of Innovations in Cancer. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):544s, 2005. Background: Research efforts tested in randomized controlled trials (RCT) have played a vital role in the development of new treatments for cancer. The research conducted by the National Cancer Institute (NCI) cooperative groups (CG) is universally considered of vital importance to this progress. However, how often new interventions tested in the NCI-CG-RCTs are highly successful or "breakthrough" is not known. Methods: All completed phase 3 RCTs (563 trials, ~149,000 patients) conducted by 6 NCI-CGs was reviewed. Published and unpublished data were used. Breakthroughs were defined in two ways: semi-quantitatively (score 1-6): the intervention was so successful according to the original researchers that it should be adopted immediately as a new therapeutic standard (=6), and quantitatively: the intervention effect resulted in a log hazard ratio of <= -0.5 in terms of survival or event-free survival. Results: According to the original investigators, 14% (n=81) of experimental testing resulted in breakthrough. 7% of interventions dramatically improved survival in terms of log hazard ratio of <= -0.5, while 13% led to a similar improvement in event-free survival. By disease, quantitatively (23%) and semi-quantitatively (12%) the highest number of breakthroughs were for leukemias. Induction and curative therapies jointly resulted in 62% and 73% of breakthroughs by quantitative and semi-quantitative assessment, respectively. 15% of childhood vs. 5% of adult cancer trials resulted in dramatic survival improvements. However, assessing semi-quantitatively, there were 18% and 14% breakthroughs in childhood and adult cancers, respectively. Conclusions: 14% of the experimental treatments that progressed to testing in RCTs resulted in discovery of breakthrough interventions. This is the first comprehensive assessment of success of innovative therapies in cancer and in clinical medicine. No systematic research was found in the literature permitting to contrast our findings with the estimate of the proportion of breakthrough interventions from non-RCT, phase I & II trials. Researchers, physicians, policy makers and the public should understand what it takes to produce a successful, breakthrough intervention in cancer.

P. Kumar, K. T. Robbins, J. Harris, T. McCulloch, A. Cmelak, R. Sofferman, P. Levine and K. Fu: Mature Results of Radiation Therapy Oncology Group (RTOG) Trial 9615 Using Intra-Arterial Cisplatin (IA-P) and Concurrent Radiation Therapy (RT) for Stage IV-T4 Head/Neck (H/N) Squamous Cell Carcinoma (SCCa). Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):519s, 2005. Background: We have previously reported on the successful feasibility of using intra-arterial (IA) cisplatin (P) and RT in a multi-institutional RTOG trial 9615 (i.e., Multi-RADPLAT protocol) for stage IV-T4 SCCa of the head/neck (1). We now report the updated mature results of this trial. Methods: Between May 1997 and December 1999, 67 patients were enrolled, 61 of whom were eligible for analysis. All patients were diagnosed with T4 disease and 39 (64%) presented with bulky (N2-3) lymphadenopathy. The disease originated from the oropharynx in 52%, oral cavity in 25%, hypopharynx and larynx in 11% each of patients. The treatment consisted of 4 infusions of IA-P (150 mg/m2 on days 1, 8, 15 and 22) and concurrent RT (70 Gy at 2.0 Gy/fraction in 7 weeks). Results: The protocol treatment was feasible (i.e., 3-4 infusions of IA-P and >=95% protocol dose of RT) in 53 (87%) patients. The complete response (CR) rates at the primary site and lymph nodes were 85% and 88%, respectively, for an overall CR rate of 80%. At a median follow-up interval of 3.9 years (range 0.9-6.1), the estimated 4-year rates of local-regional tumor control and overall survival are 55.4% (95% CI; 42.7, 68.1) and 49.2% (95% CI: 35.7%, 62.7%), respectively. The rate of severe toxicity (Grade IV/V) was 43% and dependent upon the experience of the institution (i.e., 14% at experienced vs. 51% at inexperienced institutions). Conclusions: The overall survival and local-regional tumor control outcome using Multi-RADPLAT therapy in patients with advanced stage IV-T4 disease appears to be comparable to results using concurrent chemoradiation therapy in recently completed phase III randomized trials in patients with more favorable earlier stage III-IV SCCa of the head/neck. The rate of severe toxicity using RADPLAT therapy is dependent upon the experience of the institution. Based upon these promising long term results, a phase III randomized trial comparing intra-arterial cisplatin to intravenous cisplatin and concurrent RT for stage IV-T4 head/neck SCCa should be considered. 1. Kumar et al., Int. J. Rad. Onc. Biol. Phys. 48:3S, 81, 2000.

G. Okawara, K. Winter, J. Donohue, P. Pisters, C. Crane, J. Greskovich, P. R. Anne, J. Bradley, C. Willet and J. Ajani: A Phase II Trial of Preoperative Chemotherapy and Chemoradiotherapy for Potentially Resectable Adenocarcinoma of the Stomach (RTOG 99-04). Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):312s, 2005. Background: Postoperative chemoradiotherapy is now considered standard treatment following curative resection of gastric cancer in selected patients. As the value of preoperative chemoradiotherapy is undetermined, this study was designed primarily to evaluate if a complete pathological response (pathCR) rate of 20% is possible employing this strategy, with feasibility, survival, tolerance and rate of curative resection as secondary endpoints. Methods: Patients having localized biopsy proven gastric adenocarcinoma (EUS T2-3, any N, M0) were eligible. A negative laparoscopic evaluation was required. Patients received 2 cycles of infusional 5-fluorouracil (200 mg/m2/d) on days 1-21, leucovorin (20 mg/m2) on days 1,7,14, and 21 and Cisplatin (20 mg/m2) on days 1-5. This was followed by concurrent radiation (45 Gy in 25 Fx) and infusional 5-fluorouracil (300 mg/m2/d) Monday to Friday and weekly Taxol (45 mg/m2) in weeks 1-5. Surgery was subsequently attempted in 5-6 weeks. Results: Forty-nine patients have been entered and 43 (12% IB, 37% II, 52% III) are evaluable. The pathCR and R0 resection rates are 27% and 77% respectively. Grade 4 toxicity (CTC 2.0) was experienced by 21% of patients with no treatment-related deaths. Radiotherapy planning and surgical technique according to protocol occurred in 44% and 49% of patients respectively. A total feasibility evaluation of this strategy is pending. Conclusions: These data suggest that the primary endpoint of the study was met (>20% pathCR rate). This study forms a basis for a future comparison of pre vs. post operative chemoradiotherapy strategies for localized resectable gastric cancer. (Supported by NCI)

G. Schwartz, K. Winter, B. Minsky, N. Janjan, P. Schaefer, J. Thomson, P. R. Anne, H. Gross, C. Willet and D. Kelsen: A Randomized Phase II Trial Comparing Two Paclitaxel (P)-Cisplatin (C) Containing Chemoradiation (CRT) Regimens as Adjuvant Therapy in Resected Gastric Cancer (RTOG Intergroup #0114). Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):312s, 2005. Background: The adjuvant arm of INT 0116, a 5-fluorouracil (5-FU)/LV containing CRT regimen, is the standard treatment for resected gastric cancer in the US. However, overall grade (gr) 3 or greater toxicity (tox) is 73% [32% gastrointestinal (GI) and 53% hematologic (heme)]. Death occurs in 1% of treated patients. The benefit and safety of newer regimens remain to be tested. Methods: We performed a randomized phase II study comparing two P-C regimens, one with (Arm 1) and the other without (Arm 2) 5-FU. The primary objective was to show a 15% improvement in 2 year DFS, as compared to INT 0116. The secondary objective was to determine whether the toxicity rates were the same or better than INT 0116. An early stopping rule was designed to close a study arm if gr 3/4 GI toxicity exceeded 47%. RT was the same on both arms (45 Gy in 1.8 Gy fractions, 5 days/wk for 5 weeks) and was started within 6 weeks of completing the post-op chemotherapy (CT). The two regimens were as follows: Arm 1, post-op 5-FU 600 mg/m2 as continuous infusion (CI) days 1-5, 29-33, C 15 mg/m2 days 1-5, 29-33 and P 175 mg/m2 days 1 and 29. CT with the RT: 5-FU 300 mg/m2 as a 5 day CI, weeks 1 to 5, and P 45 mg/m2 days 1, 8, 15, 22, 29. Arm 2: post-op P 175 mg/m2 and C at 75 mg/m2 days 1, 29. CT with the RT: P 60 mg/m2 as a 96 hour CI weeks 1-5, and C 30 mg/m2 days 1, 8, 15, 22, 29. Results: From 5/01 until 2/04 (study closure), 78 patients entered this study from 28 institutions. At the planned interim analysis, it was found that on Arm 1 17/28 (60%) patients had gr 3 and 1 had gr 4 GI tox. In addition, 6/28 (21%) had gr 3 and 13/28 (46%) had gr 4 heme tox. Since this exceeded the preset levels of acceptable tox, Arm 1 was closed to patient entry (5/03). Accrual continued to Arm 2. On Arm 2, 10/46 (22%) had gr 3 and 3/46 (7%) had gr 4 GI tox. Gr 3 and 4 heme tox was 10/46 (22%) and 4/46 (9%), respectively. Overall, gr 4 tox was 15/28 (54%) on Arm 1 and 9/46 (20%) on Arm 2. Conclusions: Arm 2, containing P and C but no 5-FU, appears to be safe and well-tolerated in patients with resected gastric cancer. If the 2 year DFS is 67% (available for analysis by 2/06), then this CRT regimen will be proposed as the investigational arm for future randomized phase III trials.

H. Soares, A. Kumar, F. Serdarevic, J. Fiorica, R. Wells, S. Swann, J. Buckner, D. Sargent, I. Hozo and B. Djulbegovic: Equipoise Principle and NCI-Sponsored Clinical Trials: Are Investigators Truly Uncertain About Their Comparisons? Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):540s, 2005. Background: Studies in which the control intervention is believed to be inferior violate ethical and scientific principle of equipoise, may result in biased results findings, and could ultimately harm research subjects. Placebo or no-therapy controlled trials are particularly susceptible to this bias. We aimed to determine if equipoise principle was violated in National Cancer Institute (NCI) sponsored randomized clinical trials (RCT). We hypothesized that if the outcomes consistently and predictably favored active interventions over placebo/no-therapy, this would indicate a systematic bias in the choice of control intervention. Methods: All published and unpublished RCTs that were completed to date by six NCI cooperative groups were analyzed. Outcomes were analyzed from all trials that included placebo or no therapy arm as control versus any experimental intervention(s). A meta-analysis was performed to assess the effects of treatments on survival, event-free survival and treatment-related mortality. In addition, the investigators judgments about the relative value of active interventions versus placebo/no-therapy were deduced. Results: Data from 94 comparisons (84 RCTs), enrolling more than 16000 patients, were synthesized. No difference in survival was seen between experimental treatments and placebo/no therapy interventions [hazard ratio (HR): 0.99 (95%CI 0.94-1.03), p=0.5]. On the other hand, event-free survival slightly favored experimental treatments [HR: 0.87 (95%CI 0.83-0.91), p<0.00001]. Treatment-related mortality was worse in the experimental groups, [HR: 1.56 (95%CI 0.99-2.47), p=0.06]. In 52% of comparisons the placebo/no therapy arm was classified as superior by the trials' investigators (p=0.677). Conclusions: The finding that placebo/no-therapy has equal chance to result in the outcomes similar to active interventions indicates that the NCI investigators were truly uncertain (i.e. equipoise) when they designed their studies. Hence, we concluded that there is no evidence of violation of equipoise in this set of publicly sponsored RCTs. This is in contrast to violation of equipoise described in the industry sponsored studies (Lancet 2000; 350:635).

S. Swann, M. Machtay, R. Komaki, C. Langer, W. Sause, C. Langer, R. Byhardt and W. Curran Jr: Impact of Overall Treatment Time During Concurrent Chemoradiotherapy for Locally Advanced NSCLC: An RTOG Secondary Analysis. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):635s, 2005. Background/Purpose: To determine if overall treatment time is associated with outcomes after definitive concurrent chemoradiotherapy for locally advanced non-small cell lung carcinoma (NSCLC). Methods: Data were analyzed from three prospective Radiation Therapy Oncology Group (RTOG) trials (RTOG 91-06, 92-04, and 94-10) in which immediate concurrent chemoradiation (cisplatin-based) was the primary therapy for good-performance status Stage III (and selected inoperable Stage II) NSCLC. Protocol-specified radiotherapy was 63-69.6 Gy over approximately 6.5 weeks. Treatment time was analyzed as a continuous variable (in days) in a multivariate model that also incorporated histology, performance status, gender, age, stage, radiotherapy fractionation, and radiotherapy dose. Endpoints studied were overall survival, progression free survival (PFS), local-regional control and toxicity. Results: A total of 474 patients were analyzed. Median followup for surviving patients was 6.1 years. The multivariate model showed that prolonged treatment time was highly significantly associated with worsening overall survival (p=0.01) and PFS (p=0.02). The hazard ratio was 1.02 (95% confidence interval 1.00-1.03), reflecting an estimated 2% increase in the risk of death for each day of prolonged treatment. Histology and performance status were also significant prognosticators in this model (p=0.02 and p=0.03 for survival, respectively). .A total of 87 patients (18%) had a treatment time that was prolonged >= 5 days beyond protocol specification; these patients had a median survival of 14.8 months, versus 19.5 months for other patients (p=0.15 by log rank). Although detailed data on the causes of treatment interruptions were not available, prolonged treatment time was strongly associated with high grade acute esophagitis (p<0.0001). Conclusions: This retrospective analysis demonstrates a negative association between prolonged overall treatment time and survival in patients treated with concurrent chemoradiation, supporting radiobiologic models. Further study of novel radiation-chemotherapy dose/fractionation regimens is warranted.

J. Torres-Roca, M. DeSilvio, L. Mora-Diaz, E. Hammond, N. Ahmad, R. Jove, J. Forman, R. Lee, H. Sandler and A. Pollack: Stat3 as a Correlate of Distant Metastasis in RTOG 86-10. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):416s, 2005. Background: Stat3 participates in the regulation of cellular growth, survival and oncogenesis. We evaluated Stat3 as a prognostic factor in prostate cancer, by determining Stat3 activity in a cohort of patients treated on RTOG 86-10, a phase III trial that randomized prostate cancer patients between RT alone and RT and short-term androgen blockade Methods: 62 patients with sufficient tissue were stained with phospho-Stat3 antibody. Stat3 activity was quantified manually and with an image analysis system (ACIS, Chromavision, San Juan Capistrano, CA). Nuclear Stat3 staining was considered positive. The results were correlated with overall mortality (OM), cause specific mortality (CSM), local progression (LP) and distant metastasis (DM) rate. Statistical comparisons were carried out using the chi-square test and Cox proportional hazards models. Stat3 activity quantified using the ACIS Index (percentage positive) was modeled as a continuous variable. ACIS Index cut-points were also tested (the median, the 25% and 75% Quartile) using univariate models of all four endpoints. Estimates for OM and CSM were calculated using the Kaplan-Meier Method: The cumulative incidence method was used to estimate LP and DM failure rates. Results: There was no significant difference in the distribution of clinical characteristics and assigned treatment between the patients available for Stat3 analysis (Stat3 cohort) and the others in RTOG 86-10 (n=394). However, the Stat3 cohort had a higher risk for development of DM (RR=1.53, p=0.02) and worse CSM (p=0.04). When treated as a continuous variable, Stat3 activity, as determined by the ACIS-Index, was correlated with the development of DM (RR=0.81, p=0.04) but not with OM, CSM or LP. Similar results were obtained when the data were dichotomized (ACIS Index, <=29% vs. >29%, 5-yr DM Rate 53.2% vs. 26.7%, p=0.07). Finally, there was no difference in the distribution of clinical and prognostic variables between patients with Stat3-Index > 29% and those with Stat3-Index <= 29%. Conclusions: Stat3 activity is correlated with the development of distant metastasis in prostate cancer. This marker should be further evaluated in a larger cohort of patients.

A. Trotti, T. Pajak, C. Gwede, R. Paulus, J. Cooper, A. Forastiere, A. Garden and K. K. Ang: The TAME Adverse Event Summary and Risk Classification System:Analysis of the RTOG H&N Database. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):534s, 2005. Background: There is currently no method for concisely summarizing and comparing aggregate adverse event (AE) data among treatment options. 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 index: short-term (acute) toxicity [T], adverse long-term effects [A] and mortality risk from treatment [M]. Methods: We estimated T-scores and A-scores from published adverse event data in 13 treatment arms from 5 RTOG H&N trials (90-03, 91-11, 95-01, 97-03, 99-14) conducted between 1990-2000 (>2200 patients). Estimation of T and A scores are calculated by dividing total number of RTOG grade 3-4 events for 13 pre-specified toxic categories by the number of patients in a cohort. We also calculated scores using individual patient data (IPD) from 2 arms of the RTOG 91-11 larynx preservation trial (314 patients). Results: Estimated T-scores demonstrate more than a 500% difference in acute toxicity burden when comparing aggressive chemoradiotherapy to conventional radiotherapy (range: 0.47-3.14). Less variation was seen in estimated late effects burden (range: 0.17-0.59). Putative T-risk burden classes were designated: <=0.6 (low), 0.7-1.0 (mod), 1.0-2.5 (high), >=2.5 (extreme). T-values from RTOG 91-11 (see table) suggest up to 250% more toxicity burden from the use of chemotherapy. Distribution of T-scores among the concurrent PLAT-RT group revealed 22% of patients experienced 3 high-grade events, and 23% experienced 4 or more (p=<0.0001). Correlations of T-scores with KPS and selected QOL domains at 3 months were modest as expected. Conclusions: TAME scores support the feasibility of quantifying toxicity burden and may have wide applications including safety monitoring and identification of patient groups at high risk for injury in multiple oncologic disorders. TAME Reporting System in RTOG 91-11   T A M RT alone 0.77 (mod risk) 0.59 3% Induction CT/RT 2.16 (high risk) 0.43 3% Concurrent CT-RT 1.97 (high risk) 0.48 5%

R. Valicenti, M. DeSilvio, G. Hanks, A. Porter, H. Brereton, W. Shipley and H. Sandler: Surrogate Endpoint for Prostate Cancer-specific Survival: Validation from an Analysis of Radiation Therapy Oncology Group Protocol 92-02. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):390s, 2005. Background: A requirement of a surrogate endpoint for prostate cancer-specific survival (PCSS) is its validation for a cohort of prospectively treated patients. We applied Prentice's criteria to determine if prostate-specific antigen doubling time (PSA-DT) fulfilled this requirement for the prostate cancer (T2C-T4 and PSA level < 150 ng/ml) patients treated on Radiation Therapy Oncology Group (RTOG) Protocol 92-02. Methods: We calculated PSA-DT assuming first-order kinetics for a minimum of three rising PSA measurements after time of randomized treatment (hormonal cytoreduction and radiation therapy without or with adjuvant androgen deprivation (arm 1 vs. arm 2)). We defined incidence of PSA-DT <3, <6, <9, and < 12 months as time-to-event endpoints. Using Kaplan-Meier methods and Cox proportional hazards model, we tested this definition of a surrogate for PCSS by Prentice's criteria (table). We evaluated: if randomized treatment predicted PCSS (1) and PSA-DT (2) and; if PSA-DT predicted PCSS (3) and was independent of randomized treatment (4a, b). Results: We analyzed all 1514 eligible patients. Median follow-up time was 71 months (142 prostate cancer deaths). Randomized treatment predicted PCSS (1) and PSA-DT <6, <9, or <12 (2). These three PSA-DT cutoffs also predicted PCSS (3). However, only for PSA-DT <12, did randomized treatment have no significant effect on PCSS (4a, b). Conclusions: Post-treatment PSA-DT <12 months met all of Prentice's criteria for surrogacy. For the first time, this was accomplished for a prospectively studied patient population, and justifies strong consideration for PSA-DT< 12 months as a surrogate endpoint for prostate cancer mortality. Supported by NCI grants: RTOG U10 CA21661, CCOP U10 CA37422, Stat U10 CA32115 Prentice Criteria Evaluation for PSA-DT <12 Months (*RR=Relative Risk; CI=Confidence Interval) Criterion Factor Endpoint RR*(95% CI) Cox P-Value 1 Treatment (1 vs. 2) PCSS 1.59 (1.14-2.23) <0.01 2 Treatment (1 vs. 2) PSA-DT<12 3.04 (2.2-4.19) <0.0001 3 PSA-DT<12 PCSS 6.17 (4.28-8.91) <0.0001 4a Treatment (1 vs. 2) (PSA-DT<12) PCSS 0.64 (0.32-1.2) >0.05 4b Treatment (1 vs. 2) (PSA-DT>12) PCSS 1.43 (0.95-2.14) >0.05

M. Vogelbaum, B. Berkey, D. Peereboom, C. Giannini, J. Suh, P. D. Brown, D. Blumenthal, C. Biggs, C. Schultz and M. Mehta: RTOG 0131: Phase II Trial of Pre-Irradiation and Concurrent Temozolomide in Patients with Newly Diagnosed Anaplastic Oligodendrogliomas and Mixed Anaplastic Oligodendrogliomas. Proc Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):119s, 2005. Background: RTOG 9402 showed that a dose-intense pre-radiation chemotherapy regimen consisting of procarbazine, lomustine and vincristine (PCV) for anaplastic oligodendrogliomas (AOs) and mixed anaplastic oligoastrocytomas (MAOs) produced improved progression free survival at the expense of increased toxicity, but no improvement in overall survival. A less toxic chemotherapy, temozolomide (TMZ), has also shown efficacy in several glial tumors, and it can be given concurrently with radiation therapy (RT) with acceptable toxicity. Methods: A phase II study was performed to evaluate the efficacy of pre-RT TMZ and the toxicity of concurrent RT and TMZ in patients with newly diagnosed AO or MAO. The primary endpoint was to determine the pre-RT TMZ six-month progression rate. Results: 40 eligible patients were entered into the trial; 55% were male, median age was 45, 50% had an AO. Twenty-seven patients completed 6 months of pre-RT TMZ and have undergone central review, and three are too early to evaluate. Of the remaining ten patients, two withdrew early due to tumor progression (not reviewed) and 4 withdrew due to toxicity. Four other patients withdrew from study without evidence of toxicity or progression. Pre-RT TMZ responses in centrally-reviewed patients (N = 27) were as follows: 1 CR (3.7%), 8 PR (29.6%), 15 SD (55.6%) and 1 PD (3.7%). CR required resolution of both T1 and T2 changes. Two patients (7.4%) had no evaluable disease. If the 2 patients who withdrew due to reported progression are included, the 6-month progression rate is 3/29 (10.3%). During concurrent RT and TMZ treatment there were two (5%) grade 3 and zero grade 4 non-hematologic toxicities. Conclusions: Pre-RT TMZ appears to be feasible, without an inordinately high rate of early progression (10.3%). In comparison, the overall 6-month progression rate observed in the pre-RT PCV arm of RTOG 9402 was 20%. Toxicity of the concurrent RT and TMZ regimen was acceptable. Analysis of tumor 1p/19q status is ongoing.

M. Werner-Wasik, S. Swann, W. Curran Jr, F. Robert, R. Komaki, C. Lee, S. Jafar, R. Share, H. Choy and G. Blumenschein: 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 Am Soc Clin Oncol (ASCO), J Clin Oncol [23] (16S):654s, 2005. Background: 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. Methods: Eligibility criteria include Zubrod performance status (PS) <=1, weight loss <=5% over past 3 months, FEV1?>=1.2 l, adequate hematologic, hepatic, and renal function. PTS receive 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). Starting on week 2, patients receive CRT (63 Gy/35 fractions) with weekly carboplatin (C) AUC 2 and paclitaxel (P) 45 mg/m2 x 6 doses followed by C (AUC 6) and P (200 mg/m2) x 2 cycles (weeks 12-17). Interim monitoring for severe (grade >=3) or excessive non-hematological 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: 34 PTS have been entered to date with toxicity data available on 8. PTS characteristics (n=22): 77% male, median age 63.5 years (range 44-84), 45% PS 0, 55% stage IIIA. Toxicity data (n=8): 1 PT with grade 3 thrombocytopenia and 1 PT with grade 4 granulocytopenia. Number of grade 3 non-hematological toxicities: fatigue (2), dyspnea (2), anorexia (1), cardiac (2), neurologic (1), pain (1), and cataract (1). Number of grade 4 non-hematologic toxicities: dyspnea (1). Conclusions: Patient accrual is ongoing. Updated toxicities will be reported.