Prospective Radiation Therapy Oncology Group Research Articles

Bladder Preservation Strategies in a Multicenter Community Setting Produces Outcomes Comparable to Prospective Radiation Therapy Oncology Group (RTOG) Protocols

Bladder Preservation Strategies in a Multicenter Community Setting Produces Outcomes Comparable to Prospective Radiation Therapy Oncology Group (RTOG) Protocols

Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233.

Multiple prospective Radiation Therapy Oncology Group (RTOG) protocols have evaluated bladder-preserving combined-modality therapy (CMT) for muscle-invasive bladder cancer (MIBC), reserving cystectomy for salvage treatment. We performed a pooled analysis of long-term outcomes in patients with MIBC enrolled across multiple studies. Four hundred sixty-eight patients with MIBC were enrolled onto six RTOG bladder-preservation studies, including five phase II studies (RTOG 8802, 9506, 9706, 9906, and 0233) and one phase III study (RTOG 8903). Overall survival (OS) was estimated using the Kaplan-Meier method, and disease-specific survival (DSS), muscle-invasive and non-muscle-invasive local failure (LF), and distant metastasis (DM) were estimated by the cumulative incidence method. The median age of patients was 66 years (range, 34 to 93 years), and clinical T stage was T2 in 61%, T3 in 35%, and T4a in 4% of patients. Complete response to CMT was documented in 69% of patients. With a median follow-up of 4.3 years among all patients and 7.8 years among survivors (n = 205), the 5- and 10-year OS rates were 57% and 36%, respectively, and the 5- and 10-year DSS rates were 71% and 65%, respectively. The 5- and 10-year estimates of muscle-invasive LF, non-muscle-invasive LF, and DM were 13% and 14%, 31% and 36%, and 31% and 35%, respectively. This pooled analysis of multicenter, prospective RTOG bladder-preserving CMT protocols demonstrates long-term DSS comparable to modern immediate cystectomy studies, for patients with similarly staged MIBC. Given the low incidence of late recurrences with long-term follow-up, CMT can be considered as an alternative to radical cystectomy, especially in elderly patients not well suited for surgery.

The influence of gender, race, and marital status on survival in lung cancer patients: analysis of Radiation Therapy Oncology Group trials.

A meta-analysis was conducted to determine the influence of gender, race, and marital status on overall survival (OS) in Radiation Therapy Oncology Group nonoperative non-small cell lung cancer trials. Data from 1365 patients treated on nine prospective Radiation Therapy Oncology Group studies activated during the 1990s were analyzed. Impact of gender, marital status, and race was considered in the Cox proportional hazards models. Age, Karnofsky performance status, weight loss, stage, histology, location of primary tumor, biologic equivalent dose, deviation from protocol dose, and education level were adjusted in the model. A two-sided p value <0.05 was considered statistically significant. Males had significantly higher mortality than females adjusted for other covariates (hazard ratio [HR] 1.22, 95% confidence interval 1.08 -1.38). Race and marital status were not independently predictive for OS. Single females had significantly better OS than single males (HR 0.72), and married males had lower OS than single females (HR 1.36). These results suggest that although certain subgroups of gender, race, and/or marital status have better outcomes with respect to OS; gender seems to be the most significant factor influencing survival results among nonoperative non-small cell lung cancer patients.

Elective Clinical Target Volumes for Conformal Therapy in Anorectal Cancer: A Radiation Therapy Oncology Group Consensus Panel Contouring Atlas

To develop a Radiation Therapy Oncology Group (RTOG) atlas of the elective clinical target volume (CTV) definitions to be used for planning pelvic intensity-modulated radiotherapy (IMRT) for anal and rectal cancers. The Gastrointestinal Committee of the RTOG established a task group (the nine physician co-authors) to develop this atlas. They responded to a questionnaire concerning three elective CTVs (CTVA: internal iliac, presacral, and perirectal nodal regions for both anal and rectal case planning; CTVB: external iliac nodal region for anal case planning and for selected rectal cases; CTVC: inguinal nodal region for anal case planning and for select rectal cases), and to outline these areas on individual computed tomographic images. The imaging files were shared via the Advanced Technology Consortium. A program developed by one of the co-authors (I.E.N.) used binomial maximum-likelihood estimates to generate a 95% group consensus contour. The computer-estimated consensus contours were then reviewed by the group and modified to provide a final contouring consensus atlas. The panel achieved consensus CTV definitions to be used as guidelines for the adjuvant therapy of rectal cancer and definitive therapy for anal cancer. The most important difference from similar atlases for gynecologic or genitourinary cancer is mesorectal coverage. Detailed target volume contouring guidelines and images are discussed. This report serves as a template for the definition of the elective CTVs to be used in IMRT planning for anal and rectal cancers, as part of prospective RTOG trials.

The prognostic value of nestin expression in newly diagnosed glioblastoma: Report from the Radiation Therapy Oncology Group

BackgroundNestin is an intermediate filament protein that has been implicated in early stages of neuronal lineage commitment. Based on the heterogeneous expression of nestin in GBM and its potential to serve as a marker for a dedifferentiated, and perhaps more aggressive phenotype, the Radiation Therapy Oncology Group (RTOG) sought to determine the prognostic value of nestin expression in newly diagnosed GBM patients treated on prior prospective RTOG clinical trials.MethodsTissue microarrays were prepared from 156 patients enrolled in these trials. These specimens were stained using a mouse monoclonal antibody specific for nestin and expression was measured by computerized quantitative image analysis using the Ariol SL-50 system. The parameters measured included both staining intensity and the relative area of expression within a specimen. This resulted into 3 categories: low, intermediate, and high nestin expression, which was then correlated with clinical outcome.ResultsA total of 153 of the 156 samples were evaluable for this study. There were no statistically significant differences between pretreatment patient characteristics and nestin expression. There was no statistically significant difference in either overall survival or progression-free survival (PFS) demonstrated, although a trend in decreased PFS was observed with high nestin expression (p = 0.06).ConclusionAlthough the correlation of nestin expression and histologic grade in glioma is of considerable interest, the presented data does not support its prognostic value in newly diagnosed GBM. Further studies evaluating nestin expression may be more informative when studied in lower grade glioma, in the context of markers more specific to tumor stem cells, and using more recent specimens from patients treated with temozolomide in conjunction with radiation.

Primary Central Nervous System Lymphoma: The Memorial Sloan-Kettering Cancer Center Prognostic Model

The purpose of this study was to analyze prognostic factors for patients with newly diagnosed primary CNS lymphoma (PCNSL) in order to establish a predictive model that could be applied to the care of patients and the design of prospective clinical trials. Three hundred thirty-eight consecutive patients with newly diagnosed PCNSL seen at Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) between 1983 and 2003 were analyzed. Standard univariate and multivariate analyses were performed. In addition, a formal cut point analysis was used to determine the most statistically significant cut point for age. Recursive partitioning analysis (RPA) was used to create independent prognostic classes. An external validation set obtained from three prospective Radiation Therapy Oncology Group (RTOG) PCNSL clinical trials was used to test the RPA classification. Age and performance status were the only variables identified on standard multivariate analysis. Cut point analysis of age determined that patients age < or = 50 years had significantly improved outcome compared with older patients. RPA of 282 patients identified three distinct prognostic classes: class 1 (patients < 50 years), class 2 (patients > or =50; Karnofsky performance score [KPS] > or = 70) and class 3 (patients > or = 50; KPS < 70). These three classes significantly distinguished outcome with regard to both overall and failure-free survival. Analysis of the RTOG data set confirmed the validity of this classification. CONCLUSION The MSKCC prognostic score is a simple, statistically powerful model with universal applicability to patients with newly diagnosed PCNSL. We recommend that it be adopted for the management of newly diagnosed patients and incorporated into the design of prospective clinical trials.

Pretreatment factors significantly influence quality of life in cancer patients: A Radiation Therapy Oncology Group (RTOG) analysis

The purpose of this analysis was to assess the impact of pretreatment factors on quality of life (QOL) in cancer patients. Pretreatment QOL (via Functional Assessment of Cancer Therapy [FACT], version 2) was obtained in 1,428 patients in several prospective Radiation Therapy Oncology Group (RTOG) trials including nonmetastatic head-and-neck (n = 1139), esophageal (n = 174), lung (n = 51), rectal (n = 47), and prostate (n = 17) cancer patients. Clinically meaningful differences between groups were defined as a difference of 1 standard error of measurement (SEM). The mean FACT score for all patients was 86 (20.7-112) with SEM of 5.3. Statistically significant differences in QOL were observed based on age, race, Karnofsky Performance Status, marital status, education level, income level, and employment status, but not by gender or primary site. Using the SEM, there were clinically meaningful differences between patients </=50 years vs. >/=65 years. Hispanics had worse QOL than whites. FACT increased linearly with higher Karnofsky Performance Status and income levels. Married patients (or live-in relationships) had a better QOL than single, divorced, or widowed patients. College graduates had better QOL than those with less education. Most pretreatment factors meaningfully influenced baseline QOL. The potentially devastating impact of a cancer diagnosis, particularly in young and minority patients, must be addressed.

Impact of overall treatment time during concurrent chemoradiotherapy for locally advanced NSCLC: An RTOG secondary analysis

7061 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. No significant financial relationships to disclose.

Effect of overall treatment time on outcomes after concurrent chemoradiation for locally advanced non–small-cell lung carcinoma: Analysis of the Radiation Therapy Oncology Group (RTOG) experience

To determine whether overall treatment time affects outcomes after definitive concurrent chemoradiotherapy for locally advanced non-small-cell lung carcinoma (NSCLC). Data were analyzed from 3 prospective Radiation Therapy Oncology Group 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. "Short" overall treatment time (per protocol) was defined as completing treatment within 5 days of plan; other patients were considered to have had "prolonged" treatment time (protocol violation); treatment time was also analyzed as a continuous variable in a multivariate model. Actuarial analysis was performed for overall survival, progression-free survival, freedom from local-regional progression, and toxicity. A total of 474 patients were analyzed. Median follow-up for surviving patients was 6.1 years. Treatment time was delivered per protocol in 387 (82%), whereas 87 patients (18%) had a prolonged treatment time. Long treatment time was significantly associated with severe acute esophagitis. Median survival was slightly better in patients completing treatment on time (19.5 months vs. 14.8 months), but this did not reach statistical significance (p = 0.15) in the univariate analysis. However, in the multivariate analysis of treatment time as a continuous variable, prolonged treatment time was significantly associated with poorer survival (p = 0.02), indicating a 2% increase in the risk of death for each day of prolongation in therapy. Histology (squamous fared worse) and performance status were also significant in the multivariate model. This retrospective analysis demonstrates a correlation between prolonged overall radiotherapy treatment time and survival in patients with locally advanced NSCLC, even when concurrent chemotherapy is used. Further study of novel radiation-chemotherapy dose/fractionation regimens is warranted.

Immunohistochemically determined total epidermal growth factor receptor levels not of prognostic value in newly diagnosed glioblastoma multiforme: Report from the Radiation Therapy Oncology Group

The Radiation Therapy Oncology Group (RTOG) performed an analysis of patterns of immunohistochemically detected total epidermal growth factor receptor (EGFR) protein expression levels and their prognostic significance on archival tissue in newly diagnosed glioblastoma multiforme (GBM) patients from prior prospective RTOG clinical trials. Patients in this study had been treated on previous RTOG GBM trials (RTOG 7401, 7918, 8302, 8409, 9006, 9305, 9602, and 9806). Tissue microarrays were prepared from 155 patients enrolled in these trials. These specimens were stained using a mouse monoclonal antibody specific for the extracellular binding domain of EGFR to detect total EGFR (including both wild-type phosphorylated and wild-type unphosphorylated isoforms with some cross-reactivity with EGFRvIII). The intensity of total EGFR protein expression was measured by computerized quantitative image analysis using the SAMBA 4000 Cell Image Analysis System. The parameters measured were the mean optical densities over the labeled areas and the staining index, which represents the proportion of stained area relative to the mean stain concentration. Both parameters were correlated with the clinical outcome. No differences in either overall or progression-free survival could be demonstrated by the mean optical density class or mean optical density quartile or the staining index of total EGFR immunostaining among the representative RTOG GBM cases. Total EGFR protein expression levels, as measured immunohistochemically, do not appear to be of prognostic value in newly diagnosed GBM patients. Given the accumulating clinical evidence of the activity of anti-EGFR agents in GBM and the preclinical data suggesting the important role of downstream mediators as effectors of EGFR signaling, the RTOG is conducting additional investigations into the prognostic value of activation patterns of EGFR signaling, both at the level of the receptor (e.g., EGFRvIII, phospho-EGFR) and at the level of downstream signal transduction pathways (e.g., PI3K, Ras/MAPK pathways).

Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: A report from the Radiation Therapy Oncology Group

Erb-1 (epidermal growth factor receptor, EGFR) and Erb-2 (Her-2) are two of the best characterized members in the EGFR pathway. In many tumor types, overexpression of these proteins is associated with enhanced malignant potential. Our objective in this study was to investigate the clinical relevance of EGFR and Her-2 expression in bladder cancer cases from four prospective Radiation Therapy Oncology Group (RTOG) bladder preservation trials using cisplatin-containing chemoradiation (RTOG 8802, 8903, 9506, and 9706). Tumors from 73 cases from patients with muscle-invading T2-T4a bladder cancers had slides interpretable for EGFR staining; 55 cases had slides interpretable for Her-2 staining. Additionally, the respective prognostic values of p53, pRB, and p16 immunostaining were concomitantly examined. Staining and interpretation of staining were done in a blinded manner, without knowledge of clinical outcome. Staining was judged as positive or negative. Subsequently, staining was correlated with clinical outcome. On univariate analysis, EGFR positivity was significantly associated with improved overall survival (p = 0.044); disease-specific survival (DSS) (p = 0.042); and DSS with intact bladder (p = 0.021). There was also a trend for association between EGFR expression and reduced frequency of distant metastasis (p = 0.06). On multivariate analysis adding tumor stage, tumor grade, whether a visibly complete transurethral resection of bladder tumor (TURBT) was done or not, and patient age to the model, EGFR positivity was significantly associated with improved DSS. On univariate analysis, Her-2 positivity was significantly associated with reduced complete response (CR) rates (50% vs. 81%, p = 0.026) after chemoradiation which remained significant on multivariate analysis. The other markers examined in this study were not found to have any prognostic value in this setting. Epidermal growth factor receptor expression appears to correlate significantly with improved outcome in bladder cancer, whereas Her-2 expression is significantly associated only with reduced CR rates after chemoradiation. Further investigations are warranted into how EGFR family members regulate response to chemoradiation in bladder cancer and their potential therapeutic implications.