Prognostic Significance of Immune Cell Infiltration in Muscle-invasive Bladder Cancer Treated with Definitive Chemoradiation: A Secondary Analysis of RTOG 0524 and RTOG 0712.

Chemoradiation therapy (CRT) is a treatment for muscle-invasive bladder cancer (MIBC). Using a novel transcriptomic profiling panel, we validated prognostic immune biomarkers to CRT using 70 pretreatment tumor samples from prospective trials of MIBC (NRG/RTOG 0524 and 0712). Disease-free survival (DFS) and overall survival (OS) were estimated via the Kaplan-Meier method and stratified by genes correlated with immune cell activation. Cox proportional-hazards models were used to assess group differences. Clustering of gene expression profiles revealed that the cluster with high immune cell content was associated with longer DFS (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.26-1.10; p = 0.071) and OS (HR 0.48, 95% CI 0.24-0.97; p = 0.040) than the cluster with low immune cell content. Higher expression of T-cell infiltration genes (CD8A and ICOS) was associated with longer DFS (HR 0.40, 95% CI 0.21-0.75; p = 0.005) and OS (HR 0.49, 95% CI 0.25-0.94; p = 0.033). Higher IDO1 expression (IFNγ signature) was also associated with longer DFS (HR 0.44, 95% CI 0.24-0.88; p = 0.021) and OS (HR 0.49, 95% CI 0.24-0.99; p = 0.048). These findings should be validated in prospective CRT trials that include biomarkers, particularly for trials incorporating immunotherapy for MIBC. PATIENT SUMMARY: We analyzed patient samples from two clinical trials (NRG/RTOG 0524 and 0712) of chemoradiation for muscle-invasive bladder cancer using a novel method to assess immune cells in the tumor microenvironment. Higher expression of genes associated with immune activation and high overall immune-cell content were associated with better disease-free survival and overall survival for patients treated with chemoradiation.

Long-term Outcomes of Chemoradiation for Muscle-invasive Bladder Cancer in Noncystectomy Candidates. Final Results of NRG Oncology RTOG 0524-A Phase 1/2 Trial of Paclitaxel + Trastuzumab with Daily Radiation or Paclitaxel Alone with Daily Irradiation.

BACKGROUND: Chemo-radiation is a well-established alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Many patients due to age or medical comorbidity are unfit for either radical cystectomy, or standard cisplatin- or 5-fluorouracil-based chemoradiation, and do not receive appropriate treatment with curative intent. We treated patients with a less aggressive protocol employing seven weekly doses of paclitaxel and daily irradiation. In those whose tumors showed overexpression of her2/neu, seven weekly doses of trastuzumab were also administered. OBJECTIVE: To report the long-term survival outcomes and toxicity results of the of NRG Oncology RTOG 0524 study. DESIGN, SETTING, AND PARTICIPANTS: Seventy patients were enrolled and 65 (median age: 76 yr) were deemed eligible. Patients were assigned to daily radiation and weekly paclitaxel + trastuzumab (group 1, 20 patients) or to daily radiation plus weekly paclitaxel (group 2, 45 patients) based on tumor her2/neu overexpression. Radiation was delivered in 1.8 Gy fractions to a total dose of 64.8 Gy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was unresolved treatment-related toxicity. The secondary endpoints were complete response rate, protocol completion rate, and disease-free and overall survival. RESULTS AND LIMITATIONS: Protocol therapy was completed by 60% (group 1) and 76% (group 2); complete response rates at 12 wk were 62% in each group. Acute treatment-related adverse events (AEs) of grade ≥3 were observed in 80% in group 1 and 58% in group 2. There was one treatment-related grade 5 AE in group 1. Unresolved acute treatment-related toxicity was 35% in group 1 and 31% in group 2. The median follow-up was 2.3 yr in all patients and 7.2 yr in surviving patients. Overall survival at 5 yr was 25.0% in group 1 and 37.8% in group 2 (33.8% overall). At 5 yr, disease-free survival was 15.0% in group 1 and 31.1% in group 2. CONCLUSIONS: In a cohort of patients with muscle-invasive bladder cancer who are not candidates for cystectomy or cisplatin chemotherapy, chemoradiation therapy offers a treatment with a significant response rate and 34% 5-yr overall survival. While there were many AEs in this medically fragile group, there were few grade 4 events and one grade 5 event attributable to therapy. PATIENT SUMMARY: Patients with invasive bladder cancer who cannot tolerate surgery were treated with radiation and systemic therapy without surgically removing their bladders. Most patients tolerated the treatment, were able to keep their bladders, and showed a significant treatment response rate.

The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial.

BACKGROUND: In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4-6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT. METHODS: The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0-1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8-70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8-25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p<0·001 (one sided) for comparison of 5-year freedom from progression rates between the treatment groups. This trial is registered with ClinicalTrials.gov, NCT00567580. The primary objectives of the trial have been completed, although long-term follow-up is continuing. FINDINGS: Between March 31, 2008, and March 30, 2015, 1792 eligible patients were enrolled and randomly assigned to the three treatment groups (592 to group 1 [PBRT alone], 602 to group 2 [PBRT plus short-term ADT], and 598 to group 3 [PLNRT plus PBRT plus short-term ADT]). 76 patients subsequently found to be ineligible were excluded from the analyses; thus, the evaluable patient population comprised 1716 patients. At the interim analysis (n=1191 patients; data cutoff May 23, 2018), the Haybittle-Peto boundary for 5-year freedom from progression was exceeded when group 1 was compared with group 3 (difference 17·9%, SE 2·9%; p<0·0001). The difference between groups 2 and 3 did not exceed the boundary (p=0·0063). With additional follow-up beyond the interim analysis (the final planned analysis; data cutoff May 26, 2021), at a median follow-up among survivors of 8·2 years (IQR 6·6-9·4), the 5-year freedom from progression rates in all 1716 eligible patients were 70·9% (95% CI 67·0-74·9) in group 1, 81·3% (78·0-84·6) in group 2, and 87·4% (84·7-90·2) in group 3. Per protocol criteria, freedom from progression in group 3 was superior to groups 1 and 2. Acute (≤3 months after radiotherapy) grade 2 or worse adverse events were significantly more common in group 3 (246 [44%] of 563 patients) than in group 2 (201 [36%] of 563; p=0·0034), which, in turn, were more common than in group 1 (98 [18%] of 547; p<0·0001). Similar findings were observed for grade 3 or worse adverse events. However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group. INTERPRETATION: The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer. FUNDING: National Cancer Institute.

The association of age with acute toxicities in NRG oncology combined modality lower GI cancer trials.

PURPOSE: Expected toxicity from chemoradiation (CRT) is an important factor in treatment decisions but is poorly understood in older adults with lower gastrointestinal (GI) malignancies. Our objective was to compare acute adverse events (AAEs) of older and younger adults with lower GI malignancies treated on NRG studies. METHODS: Data from 6 NRG trials, testing combined modality therapy in patients with anal or rectal cancer, were used to test the hypothesis that older age was associated with increased AAEs. AAEs and compliance with protocol-directed therapy were compared between patients aged ≥70 and < 70. Categorical variables were compared across age groups using the chi-square test. The association of age on AAEs was evaluated using a covariate-adjusted logistic regression model, with odds ratio (OR) reported. To adjust for multiple comparisons, a p-value <0.01 was considered statistically significant. RESULTS: There were 2525 patients, including 380 patients ≥70 years old (15%) evaluable. Older patients were more likely to have worse baseline performance status (PS 1 or 2) (23% vs. 16%, p = 0.001), but otherwise baseline characteristics were similar. Older patients were less likely to complete their chemotherapy (78% vs. 87%, p < 0.001), but had similar RT duration. On univariate analysis, older patients were more likely to experience grade ≥ 3 GI AAEs (36% vs. 23%, p < 0.001), and less likely to experience grade ≥ 3 skin AAEs (8% vs. 14%, p = 0.002). On multivariable analysis, older age was associated with grade ≥ 3 GI AAE (OR 1.93, 95% CI: 1.52, 2.47, p < 0.001) after adjusting for sex, race, PS, and disease site. CONCLUSIONS: Older patients with lower GI cancers who underwent CRT were less likely to complete chemotherapy and had higher rates of grade 3+ GI AAEs. These results can be used to counsel older adults prior to treatment and manage expected toxicities throughout pelvic CRT.

A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524).

PURPOSE: Bladder preservation therapy is an effective treatment for muscle-invasive urothelial carcinoma (UC). In this study we treated noncystectomy candidates with daily radiation and weekly paclitaxel for 7 weeks. Patients whose tumors showed her2/neu overexpression were additionally treated with weekly trastuzumab. METHODS AND MATERIALS: Sixty-eight evaluable patients were treated with radiation therapy and either paclitaxel + trastuzumab (group 1) or paclitaxel alone (group 2). Groups were assigned on the basis of her2/neu immunohistochemistry results. Patients received 1.8-Gy fractions to a total dose of 64.8 Gy. The primary endpoint of the study was treatment-related toxicity, and secondary endpoints included complete response (CR) rate, protocol completion rate, and survival. RESULTS: A total of 20 evaluable patients were treated in group 1 and 46 patients in group 2. Acute treatment-related adverse events (AEs) were observed in 7 of 20 patients in group 1 (35%) and 14 of 46 patients in group 2 (30.4%). Protocol therapy was completed by 60% (group 1) and 74% (group 2) of patients. Most incompletions were due to toxicity, and the majority of AEs were gastrointestinal, including 1 grade 5 AE (group 1). Two other deaths (both in group 2) were unrelated to protocol therapy. No unexpected cardiac, hematologic, or other toxicities were observed. The CR rate at 1 year was 72% for group 1 and 68% for group 2. CONCLUSIONS: In patients with muscle-invasive UC who are not candidates for cystectomy, daily radiation combined with paclitaxel is an effective treatment strategy with a high completion rate and moderate toxicity. In patients with her2/neu-positive tumors, a group generally considered to have worse outcomes, the addition of trastuzumab appears to result in comparable efficacy and toxicity. Further biomarker-driven trials should be undertaken in advancing treatment of this challenging disease.

Molecular-Based Recursive Partitioning Analysis Model for Glioblastoma in the Temozolomide Era: A Correlative Analysis Based on NRG Oncology RTOG 0525.

IMPORTANCE: There is a need for a more refined, molecularly based classification model for glioblastoma (GBM) in the temozolomide era. OBJECTIVE: To refine the existing clinically based recursive partitioning analysis (RPA) model by incorporating molecular variables. DESIGN, SETTING, AND PARTICIPANTS: NRG Oncology RTOG 0525 specimens (n = 452) were analyzed for protein biomarkers representing key pathways in GBM by a quantitative molecular microscopy-based approach with semiquantitative immunohistochemical validation. Prognostic significance of each protein was examined by single-marker and multimarker Cox regression analyses. To reclassify the prognostic risk groups, significant protein biomarkers on single-marker analysis were incorporated into an RPA model consisting of the same clinical variables (age, Karnofsky Performance Status, extent of resection, and neurologic function) as the existing RTOG RPA. The new RPA model (NRG-GBM-RPA) was confirmed using traditional immunohistochemistry in an independent data set (n = 176). MAIN OUTCOMES AND MEASURES: Overall survival (OS). RESULTS: In 452 specimens, MGMT (hazard ratio [HR], 1.81; 95% CI, 1.37-2.39; P < .001), survivin (HR, 1.36; 95% CI, 1.04-1.76; P = .02), c-Met (HR, 1.53; 95% CI, 1.06-2.23; P = .02), pmTOR (HR, 0.76; 95% CI, 0.60-0.97; P = .03), and Ki-67 (HR, 1.40; 95% CI, 1.10-1.78; P = .007) protein levels were found to be significant on single-marker multivariate analysis of OS. To refine the existing RPA, significant protein biomarkers together with clinical variables (age, Karnofsky Performance Status, extent of resection, and neurological function) were incorporated into a new model. Of 166 patients used for the new NRG-GBM-RPA model, 97 (58.4%) were male (mean [SD] age, 55.7 [12.0] years). Higher MGMT protein level was significantly associated with decreased MGMT promoter methylation and vice versa (1425.1 for methylated vs 1828.0 for unmethylated; P < .001). Furthermore, MGMT protein expression (HR, 1.84; 95% CI, 1.38-2.43; P < .001) had greater prognostic value for OS compared with MGMT promoter methylation (HR, 1.77; 95% CI, 1.28-2.44; P < .001). The refined NRG-GBM-RPA consisting of MGMT protein, c-Met protein, and age revealed greater separation of OS prognostic classes compared with the existing clinically based RPA model and MGMT promoter methylation in NRG Oncology RTOG 0525. The prognostic significance of the NRG-GBM-RPA was subsequently confirmed in an independent data set (n = 176). CONCLUSIONS AND RELEVANCE: This new NRG-GBM-RPA model improves outcome stratification over both the current RTOG RPA model and MGMT promoter methylation, respectively, for patients with GBM treated with radiation and temozolomide and was biologically validated in an independent data set. The revised RPA has the potential to contribute to improving the accurate assessment of prognostic groups in patients with GBM treated with radiation and temozolomide and to influence clinical decision making. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00304031.

NRG oncology RTOG 0625: a randomized phase II trial of bevacizumab with either irinotecan or dose-dense temozolomide in recurrent glioblastoma.

Angiogenesis, a hallmark of glioblastoma, can potentially be targeted by inhibiting the VEGF pathway using bevacizumab, a humanized monoclonal antibody against VEGF-A. This study was designed to determine the efficacy and safety of these regimens in the cooperative group setting. Eligibility included age ≥18, recurrent or progressive GBM after standard chemoradiation. Treatment was intravenous bevacizumab 10 mg/kg and either irinotecan (CPT) 125 mg/m2 every 2 weeks or temozolomide (TMZ) 75-100 mg/m2 day 1-21 of 28 day cycle. Accrual goal was 57 eligible patients per arm. Primary endpoint was 6 month progression-free survival (6-m PFS); a predetermined rate of ≥35 % to declare efficacy. 60 eligible patients were enrolled on TMZ arm and 57 patients on CPT arm. Median age was 56, median KPS was 80. For TMZ arm, the 6-m-PFS rate was 39 % (23/59); for the CPT arm, the 6-m-PFS rate was 38.6 % (22/57). Objective responses: TMZ arm had 2 (3 %) CR, 9 (16 %) PR; CPT arm had 2 (4 %) CR, 13 (24 %) PR. Overall there was moderate toxicity: TMZ arm with 33 (55 %) grade 3, 11 (18 %) grade 4, and 1 (2 %) grade 5 (fatal) toxicities; CPT arm had 22 (39 %) grade 3, 7 (12 %) grade 4, and 3 (5 %) grade 5 toxicities. The 6-m-PFS surpassed the predetermined efficacy threshold for both arms, corroborating the efficacy of bevacizumab and CPT and confirming activity for bevacizumab and protracted TMZ for recurrent/progressive GBM, even after prior temozolomide exposure. Toxicities were within anticipated frequencies with a moderately high rate of venous thrombosis, moderate hypertension and one intracranial hemorrhage.

NRG Oncology Radiation Therapy Oncology Group 0822: A Phase 2 Study of Preoperative Chemoradiation Therapy Using Intensity Modulated Radiation Therapy in Combination With Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer.

PURPOSE: To evaluate the rate of gastrointestinal (GI) toxicity of neoadjuvant chemoradiation with capecitabine, oxaliplatin, and intensity modulated radiation therapy (IMRT) in cT3-4 rectal cancer. METHODS AND MATERIALS: Patients with localized, nonmetastatic T3 or T4 rectal cancer <12 cm from the anal verge were enrolled in a prospective, multi-institutional, single-arm study of preoperative chemoradiation. Patients received 45 Gy with IMRT in 25 fractions, followed by a 3-dimensional conformal boost of 5.4 Gy in 3 fractions with concurrent capecitabine/oxaliplatin (CAPOX). Surgery was performed 4 to 8 weeks after the completion of therapy. Patients were recommended to receive FOLFOX chemotherapy after surgery. The primary endpoint of the study was acute grade 2 to 5 GI toxicity. Seventy-one patients provided 80% probability to detect at least a 12% reduction in the specified GI toxicity with the treatment of CAPOX and IMRT, at a significance level of .10 (1-sided). RESULTS: Seventy-nine patients were accrued, of whom 68 were evaluable. Sixty-one patients (89.7%) had cT3 disease, and 37 (54.4%) had cN (+) disease. Postoperative chemotherapy was given to 42 of 68 patients. Fifty-eight patients had target contours drawn per protocol, 5 patients with acceptable variation, and 5 patients with unacceptable variations. Thirty-five patients (51.5%) experienced grade ≥ 2 GI toxicity, 12 patients (17.6%) experienced grade 3 or 4 diarrhea, and pCR was achieved in 10 patients (14.7%). With a median follow-up time of 3.98 years, the 4-year rate of locoregional failure was 7.4% (95% confidence interval [CI]: 1.0%-13.7%). The 4-year rates of OS and DFS were 82.9% (95% CI: 70.1%-90.6%) and 60.6% (95% CI: 47.5%-71.4%), respectively. CONCLUSION: The use of IMRT in neoadjuvant chemoradiation for rectal cancer did not reduce the rate of GI toxicity.

Efficacy endpoints of radiation therapy group protocol 0247: a randomized, phase 2 study of neoadjuvant radiation therapy plus concurrent capecitabine and irinotecan or capecitabine and oxaliplatin for patients with locally advanced rectal cancer.

PURPOSE: To report secondary efficacy endpoints of Radiation Therapy Oncology Group protocol 0247, primary endpoint analysis of which demonstrated that preoperative radiation therapy (RT) with capecitabine plus oxaliplatin achieved a pathologic complete remission prespecified threshold (21%) to merit further study, whereas RT with capecitabine plus irinotecan did not (10%). METHODS AND MATERIALS: A randomized, phase 2 trial evaluated preoperative RT (50.4 Gy in 1.8-Gy fractions) with 2 concurrent chemotherapy regimens: (1) capecitabine (1200 mg/m(2)/d Monday-Friday) plus irinotecan (50 mg/m(2)/wk × 4); and (2) capecitabine (1650 mg/m(2)/d Monday-Friday) plus oxaliplatin (50 mg/m(2)/wk × 5) for clinical T3 or T4 rectal cancer. Surgery was performed 4 to 8 weeks after chemoradiation, then 4 to 6 weeks later, adjuvant chemotherapy (oxaliplatin 85 mg/m(2); leucovorin 400 mg/m(2); 5-fluorouracil 400 mg/m(2); 5-fluorouracil 2400 mg/m(2)) every 2 weeks × 9. Disease-free survival (DFS) and overall survival (OS) were estimated univariately by the Kaplan-Meier method. Local-regional failure (LRF), distant failure (DF), and second primary failure (SP) were estimated by the cumulative incidence method. No statistical comparisons were made between arms because each was evaluated individually. RESULTS: A total of 104 patients (median age, 57 years) were treated; characteristics were similar for both arms. Median follow-up for RT with capecitabine/irinotecan arm was 3.77 years and for RT with capecitabine/oxaliplatin arm was 3.97 years. Four-year DFS, OS, LRF, DF, and SP estimates for capecitabine/irinotecan arm were 68%, 85%, 16%, 24%, and 2%, respectively. The 4-year DFS, OS, LRF, DF, and SP failure estimates for capecitabine/oxaliplatin arm were 62%, 75%, 18%, 30%, and 6%, respectively. CONCLUSIONS: Efficacy results for both arms are similar to other reported studies but suggest that pathologic complete remission is an unsuitable surrogate for traditional survival metrics of clinical outcome. Although it remains uncertain whether the addition of a second cytotoxic agent enhances the effectiveness of fluorouracil plus RT, these results suggest that further study of irinotecan may be warranted.

Older age predicts decreased metastasis and prostate cancer-specific death for men treated with radiation therapy: meta-analysis of radiation therapy oncology group trials.

PURPOSE: The impact of age on prostate cancer (PCa) outcome has been controversial; therefore, we analyzed the effect of age on overall survival (OS), distant metastasis, prostate cancer-specific death (PCSD), and nonprostate cancer death (NPCD) on patients with locally advanced PCa. METHODS AND MATERIALS: Patients who participated in four Radiation Therapy Oncology Group (RTOG) phase III trials, 8531, 8610, 9202, and 9413, were studied. Cox proportional hazards regression was used for OS analysis, and cumulative events analysis with Fine and Gray's regression was used for analyses of metastasis, PCSD, and NPCD. RESULTS: Median follow-up of 4,128 patients with median age of 70 (range, 43-88 years) was 7.3 years. Most patients had high-risk disease: cT3 to cT4 (54%) and Gleason scores (GS) of 7 (45%) and 8 to 10 (27%). Older age (≤70 vs. >70 years) predicted for decreased OS (10-year rate, 55% vs. 41%, respectively; p<0.0001) and increased NPCD (10-year rate, 28% vs. 46%, respectively; p<0.0001) but decreased metastasis (10-year rate, 27% vs. 20%, respectively; p<0.0001) and PCSD (10-year rate, 18% vs. 14%, respectively; p<0.0001). To account for competing risks, outcomes were analyzed in 2-year intervals, and age-dependent differences in metastasis and PCSD persisted, even in the earliest time periods. When adjusted for other covariates, an age of >70 years remained associated with decreased OS (hazard ratio [HR], 1.56 [95% confidence interval [CI], 1.43-1.70] p<0.0001) but with decreased metastasis (HR, 0.72 [95% CI, 0.63-0.83] p<0.0001) and PCSD (HR, 0.78 [95% CI, 0.66-0.92] p<0.0001). Finally, the impact of the duration of androgen deprivation therapy as a function of age was evaluated. CONCLUSIONS: These data support less aggressive PCa in older men, independent of other clinical features. While the biological underpinning of this finding remains unknown, stratification by age in future trials appears to be warranted.

Image-guided radiotherapy (IGRT) for prostate cancer comparing kV imaging of fiducial markers with cone beam computed tomography (CBCT).

PURPOSE: To present our single-institution experience with image-guided radiotherapy comparing fiducial markers and cone-beam computed tomography (CBCT) for daily localization of prostate cancer. METHODS AND MATERIALS: From April 2007 to October 2008, 36 patients with prostate cancer received intensity-modulated radiotherapy with daily localization by use of implanted fiducials. Orthogonal kilovoltage (kV) portal imaging preceded all 1244 treatments. Cone-beam computed tomography images were also obtained before 286 treatments (23%). Shifts in the anterior-posterior (AP), superior-inferior (SI), and left-right (LR) dimensions were made from kV fiducial imaging. Cone-beam computed tomography shifts based on soft tissues were recorded. Shifts were compared by use of Bland-Altman limits of agreement. Mean and standard deviation of absolute differences were also compared. A difference of 5 mm or less was acceptable. Subsets including start date, body mass index, and prostate size were analyzed. RESULTS: Of 286 treatments, 81 (28%) resulted in a greater than 5.0-mm difference in one or more dimensions. Mean differences in the AP, SI, and LR dimensions were 3.4 ± 2.6 mm, 3.1 ± 2.7 mm, and 1.3 ± 1.6 mm, respectively. Most deviations occurred in the posterior (fiducials, 78%; CBCT, 59%), superior (79%, 61%), and left (57%, 63%) directions. Bland-Altman 95% confidence intervals were -4.0 to 9.3 mm for AP, -9.0 to 5.3 mm for SI, and -4.1 to 3.9 mm for LR. The percentages of shift agreements within ±5 mm were 72.4% for AP, 72.7% for SI, and 97.2% for LR. Correlation between imaging techniques was not altered by time, body mass index, or prostate size. CONCLUSIONS: Cone-beam computed tomography and kV fiducial imaging are similar; however, more than one-fourth of CBCT and kV shifts differed enough to affect target coverage. This was even more pronounced with smaller margins (3 mm). Fiducial imaging requires less daily physician input, is less time-consuming, and is our preferred method for prostate image-guided radiotherapy.

Prognostic value of survivin in locally advanced prostate cancer: study based on RTOG 8610.

PURPOSE: To examine the prognostic value of nuclear and cytoplasmic survivin expression in men with locally advanced prostate cancer who were enrolled in Radiation Therapy Oncology Group (RTOG) protocol 8610. METHODS AND MATERIALS: RTOG 8610 was a Phase III randomized study comparing the effect of radiotherapy plus short-term androgen deprivation with radiotherapy alone. Of the 456 eligible patients, 68 patients had suitably stained tumor material for nuclear survivin analysis and 65 patients for cytoplasmic survivin. RESULTS: Compared with patients with nuclear survivin intensity scores of 191.2 had significantly improved prostate cancer survival (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.20-1.00, p = 0.0452). On multivariate analysis, nuclear survivin intensity scores >191.2 were significantly associated with improved overall survival (HR, 0.46; 95% CI, 0.25-0.86; p = 0.0156) and prostate cancer survival (HR, 0.36; 95% CI, 0.16-0.84; p = 0.0173). On univariate analysis, compared with patients with cytoplasmic survivin integrated optical density 82.7 showed a significantly increased risk of local progression (HR, 2.49; 95% CI, 1.03-6.01; p = 0.0421). CONCLUSION: Nuclear overexpression of survivin was associated with improved overall and prostate cancer survival on multivariate analysis, and cytoplasmic overexpression of survivin was associated with increased rate of local progression on univariate analysis in patients with locally advanced prostate cancer treated on RTOG 8610. Our results might reflect the different functions of survivin and its splice variants, which are known to exist in distinct subcellular compartments.

Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610.

PURPOSE: Radiation Therapy Oncology Group (RTOG) 8610 was the first phase III randomized trial to evaluate neoadjuvant androgen deprivation therapy (ADT) in combination with external-beam radiotherapy (EBRT) in men with locally advanced prostate cancer. This report summarizes long-term follow-up results. MATERIALS AND METHODS: Between 1987 and 1991, 456 assessable patients (median age, 70 years) were enrolled. Eligible patients had bulky (5 x 5 cm) tumors (T2-4) with or without pelvic lymph node involvement according to the 1988 American Joint Committee on Cancer TNM staging system. Patients received combined ADT that consisted of goserelin 3.6 mg every 4 weeks and flutamide 250 mg tid for 2 months before and concurrent with EBRT, or they received EBRT alone. Study end points included overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), disease-free survival (DFS), and biochemical failure (BF). RESULTS: Ten-year OS estimates (43% v 34%) and median survival times (8.7 v 7.3 years) favored ADT and EBRT, respectively; however, these differences did not reach statistical significance (P = .12). There was a statistically significant improvement in 10-year DSM (23% v 36%; P = .01), DM (35% v 47%; P = .006), DFS (11% v 3%; P < .0001), and BF (65% v 80%; P < .0001) with the addition of ADT, but no differences were observed in the risk of fatal cardiac events. CONCLUSION: The addition of 4 months of ADT to EBRT appears to have a dramatic impact on clinically meaningful end points in men with locally advanced disease with no statistically significant impact on the risk of fatal cardiac events.

Intensity-modulated radiotherapy using implanted fiducial markers with daily portal imaging: assessment of prostate organ motion.

PURPOSE: To assess our single institutional experience with daily localization, using fiducials for prostate radiotherapy. METHODS AND MATERIALS: From January 2004 to September 2005, 33 patients were treated with 1,097 intensity-modulated radiation treatments, using three implanted fiducials. Daily portal images were obtained before treatments. Shifts were made for deviations > or =3 mm in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) dimensions. RESULTS: Of 1,097 treatments, 987 (90%) required shifts. Shifts were made in the LR, SI, and AP dimensions in 51%, 67%, and 58% of treatments, respectively. In the LR dimension, the median distance shifted was 5 mm. Of 739 shifts in the SI dimension, 73% were in the superior direction for a median distance of 6 mm, and 27% were shifted inferiorly for a median distance of 5 mm. The majority of shifts in the AP dimension were in the anterior direction (87%). Median distances shifted in the anterior and posterior directions were 5 mm and 4 mm, respectively. The median percentage of treatments requiring shifts per patient was 93% (range, 57-100%). Median deviations in the LR, SI, and AP dimensions were 3 mm, 4 mm, and 3 mm, respectively. Deviations in the SI and AP dimensions were more often in the superior rather than inferior (60% vs. 29%) and in the anterior rather than posterior (70% vs. 16%) directions. CONCLUSIONS: Interfraction prostate motion is significant. Daily portal imaging with implanted fiducials improves localization of the prostate, and is necessary for the reduction of treatment margins.

Activated STAT3 as a correlate of distant metastasis in prostate cancer: a secondary analysis of Radiation Therapy Oncology Group 86-10.

OBJECTIVE: STAT3 participates in the regulation of cellular growth, survival, and oncogenesis. We evaluated the association between activated STAT3 expression and overall survival, disease-specific survival, distant metastasis, and local progression in a cohort of patients treated with either radiotherapy alone or radiotherapy plus short-term androgen blockade. METHODS: A total of 456 assessable patients were included in the Radiation Therapy Oncology Group 86-10 trial. Of these, 62 patients had sufficient tissue for the analysis of STAT3 expression by immunohistochemistry. Nuclear staining was quantified by an image analysis system. RESULTS: No significant difference was found in the distribution of clinical characteristics and assigned treatment between the patients available for STAT3 analysis (STAT3 cohort) and the others in the Radiation Therapy Oncology Group 86-10 trial (n = 394). Activated STAT3 correlated inversely with the development of distant metastasis (risk ratio [RR] = 0.81, P = 0.04) but not with overall survival, cause-specific survival, or local progression. Similar results were obtained when the data were dichotomized (ACIS index greater than 29%, RR = 0.41, P = 0.07). On multivariate analysis, activated STAT3 (continuous variable) was an independent predictor of distant metastasis (RR = 0.79, P = 0.04). CONCLUSIONS: Activated STAT3 was inversely related to the development of distant metastasis in prostate cancer. This marker should be evaluated further in a larger cohort of patients.

Prostate-specific antigen control with low-dose adjuvant radiotherapy for high-risk prostate cancer.

OBJECTIVES: To analyze the prostate-specific antigen (PSA) outcome after low-dose adjuvant RT at a single institution, because the role and optimal dose of external beam radiotherapy (RT) after radical prostatectomy for prostate cancer remain controversial. METHODS: We retrospectively identified 65 men who had received low-dose adjuvant RT (median 50 Gy) for microscopically positive margins with an undetectable postoperative PSA from 1990 to 2004. Biochemical failure-free survival was the primary endpoint. Biochemical failure was defined as two consecutive PSA increases to greater than 0.2 ng/mL. RESULTS: At a median follow-up of 5 years, 2 men had developed distant metastasis, 2 had local recurrence, and 2 had died (neither attributable to prostate cancer). Biochemical failure had occurred in 7 men (11%). The 5 and 8-year rate of biochemical failure-free survival was 87%. A greater Gleason score (P = 0.04) and seminal vesicle invasion (P = 0.04) predicted significantly for increased biochemical failure on univariate analysis. No single factor was significant on multivariate analysis. Men with a Gleason score of 7 or less had a 5-year biochemical failure-free survival rate of more than 90%. In contrast, those with a Gleason score of 8 or more had a 50% risk of biochemical failure at 5 years. Acute bowel or bladder toxicity (all grade 2 or less) developed in 25%. Two men developed chronic urethral stricture requiring dilation, and 34 (51%) developed surgery-related toxicity that persisted throughout and after RT. CONCLUSIONS: Low-dose RT is well tolerated and can potentially provide PSA control in men with Gleason score 7 or less disease with positive surgical margins after radical prostatectomy.

Topoisomerase II alpha expression correlates with diminished disease-free survival in invasive breast cancer.

PURPOSE: Topoisomerase II alpha (Topo II alpha) plays a role in DNA replication and is the molecular target for anthracyline-based chemotherapy. The purpose of this study was to evaluate the relationship between Topo II alpha expression and survival in patients with invasive breast cancer. METHODS AND MATERIALS: Formalin-fixed, paraffin-embedded tumor specimens from 24 women with invasive breast cancer were stained for Topo II alpha expression. All women underwent mastectomy. Radiotherapy was given at the University of Utah Department of Radiation Oncology. Of the patients, 23 (96%) received chemotherapy. The level of Topo II alpha expression within tumor cells was compared with clinical factors and overall survival. RESULTS: The median percentage of tumor cells expressing Topo II alpha was 70%. Increased Topo II alpha tumor expression significantly correlated with diminished disease-free survival. Five-year disease-free survival was 100% for patients with <70% of breast cancer cells expressing Topo II alpha compared with 42% for patients with > or =70% Topo II alpha expression (p = 0.008). The level of Topo II alpha expression within tumor cells correlated with T stage (p = 0.008) but not with other pathologic factors. CONCLUSIONS: Increased Topo II alpha expression significantly correlated with diminished disease-free survival in patients with invasive breast cancer. These findings may indicate a role for Topo II alpha expression as a prognostic factor in breast cancer.

Adjuvant radiotherapy and survival outcomes in early-stage endometrial cancer: a multi-institutional analysis of 608 women.

OBJECTIVE: The role of post-operative radiotherapy (RT) in women with early-stage, low to intermediate risk cancer of the uterine corpus remains controversial. The primary objective of this analysis was to evaluate the survival outcomes of women with early-stage endometrial cancer treated with surgery alone or surgery followed by RT. METHODS: Data from two institutions were collected from 1990 to 2003. The 608 eligible women had FIGO stage IA to IIA endometrial cancer and underwent primary surgery +/-RT. Univariate and multivariate analyses of pertinent variables were performed for the end points of disease-free survival (DFS) and overall survival (OS). RESULTS: The median age for all women was 64 years. RT was delivered to 133 women (22%). Unfavorable histologic grade (P < 0.0001) and stage (P < 0.0001) were significantly more prevalent in the adjuvant RT group. At a median follow-up of 5.2 years, 26 pelvic (11 vaginal) and 16 distant failures occurred along with 110 deaths (with no significant differences between women undergoing surgery alone or followed by RT). Adjuvant RT, younger age, and lower stage predicted for improved DFS and OS on multivariate analysis. Stratified analysis revealed that adjuvant RT conferred a survival benefit in women with stage IC or IIA disease. CONCLUSIONS: Adjuvant RT was associated with improved disease-free and overall survival in women with higher risk disease. Despite significantly worse disease characteristics among women in the adjuvant RT group, the analyzed end points were equivalent among the two groups. These findings suggest that adjuvant radiotherapy has a significant benefit in reducing mortality and disease progression in early-stage carcinoma of the uterine corpus.

Correlation between human epidermal growth factor receptor family (EGFR, HER2, HER3, HER4), phosphorylated Akt (P-Akt), and clinical outcomes after radiation therapy in carcinoma of the cervix.

OBJECTIVE: To investigate prognostic significance of and correlations between HER1 (EGFR), HER2 (c-erb-B2), HER3 (c-erb-B3), HER4 (c-erb-B4), and phosphorylated Akt (P-Akt) in patients treated with radiation for cervical carcinoma. METHODS: Fifty-five patients with stages I-IVA cervical carcinoma were treated with definitive radiotherapy. Tumor expression of each biomarker was quantitatively scored by an automated immunohistochemical imaging system. Parametric correlations were performed between biomarkers. Univariate and multivariate analysis was performed with disease-free survival (DFS) and overall survival (OS) as primary endpoints. RESULTS: Correlations were observed between expression of HER2 and HER4 (P = 0.003), and HER3 and HER4 (P = 0.004). Decreased HER2, HER4, and P-Akt expressions were significant for diminished DFS on univariate analysis (P = 0.04, P = 0.008, and P = 0.02, respectively). Increased EGFR, and diminished HER2, HER4, and P-Akt expression were significant or showed trends toward significance for diminished OS on univariate analysis (P = 0.07, P = 0.008, P = 0.09, and P = 0.08, respectively). After controlling for pretreatment factors, multivariate analysis revealed HER2 associated with improved OS (P = 0.05). CONCLUSIONS: These data emphasize that significant correlations exist between the differential expression of various HER family receptors. Multivariate analysis revealed only increased HER2 expression associated with improved OS after controlling for pretreatment clinical factors. These data emphasize the importance of continued basic and translational research on the HER family of receptors in cervical carcinoma.

Comparison of late rectal toxicity from conventional versus three-dimensional conformal radiotherapy for prostate cancer: analysis of clinical and dosimetric factors.

OBJECTIVES: To compare late rectal toxicity (LRT) after definitive radiotherapy (DR) and salvage radiotherapy (SR) in prostate cancer using conventional (CONV) or three-dimensional conformal (3-D) techniques. METHODS: The outcomes and clinical factors of 212 patients with Stage T1a-T4 prostate cancer were evaluated (separated into DR and SR groups). The median prescribed dose was 66, 74, 66, and 70 Gy, for the CONV-DR, 3-D-DR, CONV-SR, and 3-D-SR groups, respectively. LRT was scored using both Radiation Therapy Oncology Group (RTOG) and modified RTOG and Late Effects Normal Tissue (mRTOG/LENT) scales. RESULTS: The 4-year biochemical relapse-free survival rate was 83% for all patients, with a trend toward improvement in the 3-D groups (78% CONV and 85% 3-D, P = 0.12). One patient (1%) in the CONV group and 24 (24%) in the 3-D group experienced grade 2 or worse LRT by the mRTOG/LENT scale. Patients undergoing DR experienced grade 2 or worse LRT of 1% versus 21% (P = 0.003) for the CONV and 3-D groups, respectively. Patients undergoing SR experienced grade 2 or worse LRT of 0% versus 40% for the CONV and 3-D groups, respectively. The following variables correlated significantly with LRT on both univariate and multivariate analyses: prescribed radiation dose (P <0.0001), percentage of rectal volume receiving 60 Gy (P <0.005), and percentage of rectal volume receiving 70 Gy (P <0.001). The pretreatment clinical factors, when added to the dosimetric data, were not statistically significant on multivariate analysis (P >0.05). CONCLUSIONS: The prescribed radiation dose and percentage of rectal volume treated to 60 or 70 Gy had statistically significant correlations with increased LRT. The rate of grade 2 or worse LRT was greater for patients undergoing SR than for those undergoing DR. We believe that continued close attention to dosimetric variables is imperative for future studies of dose escalation.