Kenneth L. Zeitzer

Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer

Background Salvage radiation therapy is often necessary in men who have undergone radical prostatectomy and have evidence of prostate‐cancer recurrence signaled by a persistently or recurrently elevated prostate‐specific antigen (PSA) level. Whether antiandrogen therapy with radiation therapy will further improve cancer control and prolong overall survival is unknown. Methods In a double‐blind, placebo‐controlled trial conducted from 1998 through 2003, we assigned 760 eligible patients who had undergone prostatectomy with a lymphadenectomy and had disease, as assessed on pathological testing, with a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension beyond the prostatic capsule), no nodal involvement, and a detectable PSA level of 0.2 to 4.0 ng per milliliter to undergo radiation therapy and receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary end point was the rate of overall survival. Results The median follow‐up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P=0.04). The 12‐year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P<0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P=0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P<0.001). Conclusions The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long‐term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo. (Funded by the National Cancer Institute and AstraZeneca; RTOG 9601 ClinicalTrials.gov number, NCT00002874.)

Ki-67 is an independent predictor of metastasis and cause-specific mortality for prostate cancer patients treated on Radiation Therapy Oncology Group (RTOG) 94-08.

PURPOSE The association of Ki-67 staining index (Ki67-SI) with overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), and biochemical failure (BF) was examined in men with favorable- to intermediate-risk prostate cancer receiving radiation therapy (RT) alone or with short-term androgen deprivation (ADT) in Radiation Therapy Oncology Group (RTOG) 94-08. METHODS AND MATERIALS 468 patients (23.6%) on RTOG 94-08 had sufficient tissue for Ki67-SI analysis. The median follow-up time was 7.9 years. Ki67-SI was determined by immunohistochemistry and quantified manually and by image analysis. Correlative analysis versus clinical outcome was performed using the third quartile (≥Q3) cutpoint. A proportional hazards multivariable analysis (MVA) dichotomized covariates in accordance with trial stratification and randomization criteria. RESULTS In MVAs adjusted for all treatment covariates, high Ki67-SI (≥Q3) was correlated with increased DSM (hazard ratio [HR] 2.48, P=.03), DM (HR 3.5, P=.002), and BF (HR 3.55, P<.0001). MVA revealed similar Ki67-associated hazard ratios in each separate treatment arm for DSM, DM, and BF; these reached significance only for DM in the RT-alone arm and for BF in both arms. Ki67-SI was not a significant predictor of intraprostatic recurrence assessed by repeated biopsy 2 years after treatment. Patients with a high or low Ki67-SI seemed to experience a similar relative benefit from the addition of ADT to radiation. CONCLUSIONS High Ki67-SI independently predicts for increased DSM, DM, and protocol BF in primarily intermediate-risk prostate cancer patients treated with RT with or without ADT on RTOG 94-08 but does not predict for local recurrence or for increased relative benefit from ADT. This and prior studies lend support for the use of Ki67-SI as a stratification factor in future trials.

A phase 3 trial of 2 years of androgen suppression and radiation therapy with or without adjuvant chemotherapy for high-risk prostate cancer: Final results of radiation therapy oncology group phase 3 randomized trial NRG oncology RTOG 9902

PURPOSE Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). METHODS AND MATERIALS Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. RESULTS A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). CONCLUSIONS NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa.

Cardiovascular Mortality Following Short-term Androgen Deprivation in Clinically Localized Prostate Cancer: An Analysis of RTOG 94-08

BACKGROUND Androgen deprivation therapy (ADT) is associated with coronary heart disease and diabetes in men with prostate cancer (PCa); however, controversy exists regarding ADT and cardiovascular mortality (CVM) with limited data for lower risk disease. OBJECTIVE We conducted a hypothesis-generating retrospective analysis to evaluate the relationship between short-course ADT and CVM in patients with clinically localized PCa enrolled in a phase III trial. DESIGN, SETTING, AND PARTICIPANTS A total of 1979 men with clinically localized (T1b-2b, prostate-specific antigen [PSA] <20 ng/ml) PCa enrolled in Radiation Therapy Oncology Group (RTOG) 94-08 from 1994 to 2001. Patients were randomized to radiation therapy (RT) with or without short-course ADT (4 mo of gonadotropin-releasing hormone (GnRH) agonist therapy and antiandrogen). Median follow-up was 9.1 yr for survivors. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The Cox proportional hazards model assessed overall survival. The Fine-Gray proportional hazards model assessed disease-specific survival (DSS) and CVM. Covariates included age, race, weight, baseline cardiovascular disease, baseline diabetes, baseline hypertension, Gleason score, T stage, and PSA. RESULTS AND LIMITATIONS Short-course ADT improved overall survival and DSS and was not associated with an increased risk of CVM. Overall, 191 cardiovascular-related deaths were observed. At 10 yr, 83 patients (cumulative incidence rate: 10%) receiving RT and ADT versus 95 patients (cumulative incidence rate: 11%) receiving RT alone experienced CVM. The treatment arm was not associated with increased CVM (unadjusted hazard ratio: 1.07; confidence interval, 0.81-1.42; p=0.62). Increased CVM was not observed in patients at low risk of PCa death or at high risk of cardiac-related death. CONCLUSIONS Data from patients enrolled in RTOG 94-08 support the hypothesis that ADT does not increase CVM risk in men with clinically localized PCa treated with short-course GnRH agonist therapy. These data support ADT use in settings with proven survival benefit. PATIENT SUMMARY We investigated the controversial relationship between hormone therapy and cardiovascular mortality in men with prostate cancer (PCa) treated with radiation in a large randomized trial. Our data suggest that hormone therapy does not increase the risk of cardiovascular death in patients with clinically localized PCa and support the use of such therapy in settings with proven survival benefit.

Importance of Local Control in Early-Stage Prostate Cancer: Outcomes of Patients With Positive Post-Radiation Therapy Biopsy Results Treated in RTOG 9408

PURPOSE The purpose of this study was to assess the association between positive post-radiation therapy (RT) biopsy results and subsequent clinical outcomes in males with localized prostate cancer. METHODS AND MATERIALS Radiation Therapy Oncology Group study 94-08 analyzed 1979 males with prostate cancer, stage T1b-T2b and prostate-specific antigen concentrations of ≤ 20 ng/dL, to investigate whether 4 months of total androgen suppression (TAS) added to RT improved survival compared to RT alone. Patients randomized to receive TAS received flutamide with luteinizing hormone releasing hormone (LHRH) agonist. According to protocol, patients without evidence of clinical recurrence or initiation of additional endocrine therapy underwent repeat prostate biopsy 2 years after RT completion. Statistical analysis was performed to evaluate the impact of positive post-RT biopsy results on clinical outcomes. RESULTS A total of 831 patients underwent post-RT biopsy, 398 were treated with RT alone and 433 with RT plus TAS. Patients with positive post-RT biopsy results had higher rates of biochemical failure (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.3-2.1) and distant metastasis (HR = 2.4; 95% CI = 1.3-4.4) and inferior disease-specific survival (HR = 3.8; 95% CI = 1.9-7.5). Positive biopsy results remained predictive of such outcomes after correction for potential confounders such as Gleason score, tumor stage, and TAS administration. Prior TAS therapy did not prevent elevated risk of adverse outcome in the setting of post-RT positive biopsy results. Patients with Gleason score ≥ 7 with a positive biopsy result additionally had inferior overall survival compared to those with a negative biopsy result (HR = 1.56; 95% CI = 1.04-2.35). CONCLUSIONS Positive post-RT biopsy is associated with increased rates of distant metastases and inferior disease-specific survival in patients treated with definitive RT and was associated with inferior overall survival in patients with high-grade tumors.

Radiation Therapy Oncology Group (RTOG) 9413: Randomized trial comparing whole pelvic radiotherapy (WPRT) to prostate only (PORT) and neoadjuvant hormone therapy (NHT) to adjuvant hormone therapy (AHT).

96 Background: RTOG 9413 demonstrated that NHT+WPRT improved progression-free survival (PFS) compared to NHT+PORT, WPRT+AHT and PORT+AHT. We update primary and secondary endpoints (SE): biochemical failure (BF), time to metastasis (Mets), prostate specific survival (PSS) and overall survival (OS). METHODS RTOG 9413 opened on April 1, 1995, and closed on June 1, 1999, with 1275 eligible pts who were required to have a risk of lymph node (LN) involvement >15% but LN-positive pts were ineligible. They were stratified by T Stage, GS (<7 vs 7-10) and PSA (>30 vs < 30ng/ml) and randomized to PORT +/- WPRT to 70 Gy and NHT or AHT. Hormonal therapy (HT) consisted of flutamide, and leuprolide or goserelin, monthly x 4 mos, beginning 2 mos before RT and continued until RT is completed (NHT) or beginning at the completion of RT (AHT). For this analysis PFS was defined as the first occurrence of local/regional or LN progression, Mets, BF (PSA nadir+2ng/mL), or death from any cause. PSS is defined as a death due to prostate cancer, treatment toxicity or unknown causes with local progression, Mets or BF. RESULTS For the entire cohort WPRT or NHT did not appear to improve any endpoint compared with PORT or AHT, (although there was a trend for improvement in regional failure for WPRT vs PORT, (p=0.07)). However, there were complex sequence/volume dependent interactions between HT and RT and statistically significant differences between the 4 arms in PFS (p=0.03). There was a trend for NHT+WPRT to improved PFS compared to NHT+PO (p=0.07) and WPRT+AHT (p=0.04). NHT+WPRT was associated with an increased risk of late GI toxicity, 5% compared to 0.6%, 2% and 2% for NHT+PORT, WPRT+AHT and PORT+AHT (p<0.001) but not in GU late toxicity. CONCLUSIONS The failure to improve SE or definitively impact PFS may reflect sample size, pt selection, and inadequate RT doses. RTOG 0924 will test the hypotheses that modern techniques and doses will improve OS without increasing late toxicity.

Non-uniform dose/time fractionated radiation therapy and chemotherapy for non-small cell lung cancer

PURPOSE A Non-uniform Fractionation schedule of large priming doses combined with concurrent chemotherapy and protracted RT was undertaken for the treatment of NSCLC. With several 5-year survivors, this study is reviewed with regard to local control, toxicity, and survival of patients. METHODS AND MATERIALS Forty-two patients with unresectable NSCLC were treated prospectively with initial priming doses followed by large field irradiation to the tumor and regional nodes to 3500 cGy. Patients were given a 1-week break and the treatment was repeated. A total dose of 7000 cGy was delivered over 9 weeks. Thirteen patients (Group A) were treated with RT alone. Twenty-nine patients (Group B) received concurrent chemotherapy; Cisplatin, 100 mg/m2, and 5-FU, 1 g/m2 for 24 h times 5 days. Sixteen patients also received Vinblastine, 3 mg/m2 on a weekly schedule. All patients have been followed more than 5 years. RESULTS Overall complete response rate was 36% and partial response rate was 57%. Absolute survival at 2 years was 26% and at 5 years was 14%. Local failure occurred in 28/42 (67%) patients. Late complications included pulmonary fibrosis (3), and osteochondritis (2). CONCLUSION This approach of high-dose Non-uniform fractionated radiation therapy has yielded an absolute 5-year survival of 14%, which appears better than the long-term results often seen in treatment of NSCL cancer.

Risk factors for late bowel and bladder toxicities in NRG Oncology prostate cancer trials of high-risk patients: A meta-analysis of physician-rated toxicities

Purpose A meta-analysis of sociodemographic variables and their association with late (>180 days from start of radiation therapy[RT]) bowel, bladder, and clustered bowel and bladder toxicities was conducted in patients with high-risk (clinical stages T2c-T4b or Gleason score 8-10 or prostate-specific antigen level >20) prostate cancer. Methods and materials Three NRG trials (RTOG 9202, RTOG 9413, and RTOG 9406) that accrued from 1992 to 2000 were used. Late toxicities were measured with the Radiation Therapy Oncology Group Late Radiation Morbidity Scale. After controlling for study, age, Karnofsky Performance Status, and year of accrual, sociodemographic variables were added to the model for each outcome variable of interest in a stepwise fashion using the Fine-Gray regression models with an entry criterion of 0.05. Results A total of 2432 patients were analyzed of whom most were Caucasian (76%), had a KPS score of 90 to 100 (92%), and received whole-pelvic RT+HT (67%). Of these patients, 13 % and 16% experienced late grade ≥2 bowel and bladder toxicities, respectively, and 2% and 3% experienced late grade ≥3 bowel and bladder toxicities, respectively. Late grade ≥2 clustered bowel and bladder toxicities were seen in approximately 1% of patients and late grade ≥3 clustered toxicities were seen in 2 patients (<1%). The multivariate analysis showed that patients who received prostate-only RT+HT had a lower risk of experiencing grade ≥2 bowel toxicities than those who received whole-pelvic RT+long-term (LT) HT (hazard ratio: 0.36; 95% confidence interval, 0.18-0.73; P = .0046 and hazard ratio: 0.43; 95% confidence interval, 0.23-0.80; P = .008, respectively). Patients who received whole-pelvic RT had similar chances of having grade ≥2 bowel or bladder toxicities no matter whether they received LT or short-term HT. Conclusions Patients with high-risk prostate cancer who receive whole-pelvic RT+LT HT are more likely to have a grade ≥2 bowel toxicity than those who receive prostate-only RT. LT bowel and bladder toxicities were infrequent. Future studies will need to confirm these findings utilizing current radiation technology and patient-reported outcomes.

Serum testosterone changes in patients treated with radiation therapy alone for prostate cancer on NRG oncology RTOG 9408

Objectives We reviewed testosterone changes for patients who were treated with radiation therapy (RT) alone on NRG oncology RTOG 9408. Methods and materials Patients (T1b-T2b, prostate-specific antigen <20 ng/mL) were randomized between RT alone and RT plus 4 months of androgen ablation. Serum testosterone (ST) levels were investigated at enrollment, RT completion, and the first follow-up 3 months after RT. The Wilcoxon signed rank test was used to compare pre- and post-treatment ST levels in patients who were randomized to the RT-alone arm. Results Of 2028 patients enrolled, 992 patients were randomized to receive RT alone and 917 (92.4%) had baseline ST values available and completed RT. Of these 917 patients, immediate and 3-month post-RT testosterone levels were available for 447 and 373 patients, respectively. Excluding 2 patients who received hormonal therapy off protocol after RT, 447 and 371 patients, respectively, were analyzed. For all patients, the median change in ST values at completion of RT and at 3-month follow-up were −30.0 ng/dL (p5-p95; −270.0 to 162.0; P < .001) and −34.0 ng/dL (p5-p95, −228.0 to 160.0; P < .01), respectively. Conclusion RT for prostate cancer was associated with a median 9.2% decline in ST at completion of RT and a median 9.3% decline 3 months after RT. These changes were statistically significant.

Impact of radiotherapy duration on outcomes in patients with esophageal cancer treated with definitive concurrent radiotherapy and chemotherapy on RTOG trials 8501 and 9405.

119 Background: Radiotherapy (RT) interruptions have a negative impact on outcomes in many epithelial malignancies treated with definitive RT. The purpose of this study was to analyze the impact of RT duration on outcomes in patients (pts) with esophageal cancer treated with definitive chemoradiotherapy (CRT). Methods: Pts treated with definitive CRT on RTOG trials 8501 and 9405 were included. Separate analyses were performed in pts receiving standard dose (SD-CRT; 50 Gy + 5FU + cisplatin) and high dose (HD-CRT; 64.8 Gy + 5FU + cisplatin) CRT. Local (LF) and regional (RF) failure were estimated by the cumulative incidence method. Disease-free (DFS) and overall (OS) survival were estimated by the Kaplan-Meier method. Univariate (UVA) and multivariate (MVA) Cox proportional hazards models were utilized to examine for correlation between RT duration (< vs. ≥ median) with LF, RF, DFS and OS. Results: In the SD-CRT cohort (n=235), 96 pts (41%) had ≥ 1 RT interruption for a median of 3 (IQR 1-6) days. The media...