Anaplastic oligodendroglial tumors: refining the correlation among histopathology, 1p 19q deletion and clinical outcome in Intergroup Radiation Therapy Oncology Group Trial 9402.

Intergroup Radiation Therapy Oncology Group Trial 9402 study, a phase III trial of chemotherapy plus radiotherapy (PCV-plus-RT) vs. radiotherapy alone for pure and mixed anaplastic oligodendroglioma confirmed the prognostic significance of 1p 19q deletion and showed that only progression-free survival (PFS) was prolonged in PCV-plus-RT-treated patients and only in association with 1p 19q deletion. We reviewed tumor histopathology, separating 115 tumors deemed to be classic for oligodendroglioma (CFO) from 132 lacking classic features of oligodendroglioma (NCFO) and evaluated the relationship of histopathology and 1p 19q status to treatment and outcome. The study disclosed: (i) overall survival (OS) of patients with CFO was significantly longer than for patients with NCFO (P < 0.0001) and was not affected by necrosis. Median OS for CFO patients with and without necrosis was 6.6 and 6.3 years (OS log-rank P = not significant), respectively, in contrast to NCFO showing 1.9 and 3.3 years respectively (OS log-rank P = 0.014). (ii) Classic oligodendroglial morphology was highly associated with 1p 19q deletion, present in 80% of CFO and only in 13% of NCFO. (iii) On multivariate analysis, both classic oligodendroglial morphology and 1p 19q deletion remained significantly associated with PFS and OS. (iv) Patients with CFO treated with PCV-plus-RT showed a trend toward increased survival compared with CFO treated with RT (P = 0.08). Median OS was not reached in the PCV-plus-RT group and was 6.3 years in RT group. These findings suggest that classic oligodendroglial morphology combined with 1p 19q deletion may in the future be predictive of chemotherapeutic response and survival.

Study of paclitaxel, etoposide, and cisplatin chemotherapy combined with twice-daily thoracic radiotherapy for patients with limited-stage small-cell lung cancer: a Radiation Therapy Oncology Group 9609 phase II study.

PURPOSE: To determine the response rate, progression-free survival and overall survival, and toxicity of paclitaxel, etoposide, and cisplatin combined with accelerated hyperfractionated thoracic radiotherapy in patients with limited-disease (LD) small-cell lung cancer (SCLC). PATIENTS AND METHODS: LD-SCLC patients with measurable disease, Karnofsky performance score of > or = 70, and adequate organ function who were previously untreated were eligible for the study. Treatment was as follows. In cycle 1 of chemotherapy, concurrent thoracic radiation therapy was administered. In cycles 2 to 4, chemotherapy was administered alone. In cycle 1, chemotherapy consisted of paclitaxel 135 mg/m(2) intravenous over 3 hours on day 1, etoposide 60 mg/m(2) intravenous on day 1 and 80 mg/m(2) orally on days 2 and 3, and cisplatin 60 mg/m(2) intravenous on day 1. In cycles 2 to 4, the paclitaxel dose was increased to 175 mg/m(2), with the etoposide and cisplatin doses remaining the same as in cycle 1. The thoracic radiation therapy consisted of 1.5 Gy in 30 fractions (total dose, 45 Gy) administered 5 days a week for 3 weeks. RESULTS: Fifty-five patients were enrolled onto the study, and 53 were assessable. The major toxicities included grade 3 and 4 acute neutropenia (32% and 43%, respectively) and grade 3 and 4 esophagitis (32% and 4%, respectively). Two patients died as a result of therapy (one died of acute respiratory distress syndrome, and one died of sepsis). There was one late fatal pulmonary toxicity. The median survival time was 24.7 months. The 2-year survival rate was 54.7%. The median progression-free survival time was 13 months, with a 2-year progression-free survival rate of 26.4%. CONCLUSION: Although this therapeutic regimen is effective in the treatment of patients with LD-SCLC, it is unlikely that the three-drug combination with thoracic radiation therapy will improve the survival times compared with the etoposide plus cisplatin chemotherapy regimen with thoracic radiation therapy in LD-SCLC patients.

Phase II Radiation Therapy Oncology Group trial of conventional radiation therapy followed by treatment with recombinant interferon-beta for supratentorial glioblastoma: results of RTOG 9710.

PURPOSE: The aim of this study was to determine whether recombinant human interferon beta-1a (rhIFN-beta), when given after radiation therapy, improves survival in glioblastoma. METHODS AND MATERIALS: After surgery, 109 patients with newly diagnosed supratentorial glioblastoma were enrolled and treated with radiation therapy (60 Gy). A total of 55 patients remained stable after radiation and were treated with rhIFN-beta (6 MU/day i.m., 3 times/week). Outcomes were compared with the Radiation Therapy Oncology Group glioma historical database. RESULTS: RhIFN-beta was well tolerated, with 1 Grade 4 toxicity and 8 other patients experiencing Grade 3 toxicity. Median survival time (MST) of the 55 rhIFN-beta-treated patients was 13.4 months. MST for the 34 rhIFN-beta-treated in RPA Classes III and IV was 16.9 vs. 12.4 months for historical controls (hazard ratio [HR] = 1.27, 95% confidence interval [CI] = 0.89-1.81). There was also a trend toward improved survival across all RPA Classes comparing the 55 rhIFN-beta treated patients and 1,658 historical controls (HR = 1.24, 95% CI = 0.94-1.63). The high rate of early failures (54/109) after radiation and before initiation of rhIFN-beta was likely caused by stricter interpretation of early radiographic changes in the current study. Matched-pair and intent-to-treat analyses performed to try to address this bias showed no difference in survival between study patients and controls. CONCLUSION: RhIFN-beta given after conventional radiation therapy was well tolerated, with a trend toward survival benefit in patients who remained stable after radiation therapy. These data suggest that rhIFN-beta warrants further evaluation in additional studies, possibly in combination with current temozolomide-based regimens.

Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma.

A correlative study was performed to address the impact of epidermal growth factor receptor (EGFR) overexpression on survival and pattern of failure in patients with advanced head and neck squamous cell carcinomas (HNSCCs) enrolled in a Phase III trial and randomized to receive conventional radiotherapy. The study population comprised 155 of 268 (58%) randomized patients with sufficient pretreatment biopsy specimens for immunohistochemical assay. The specimens were dewaxed and incubated after standard preparation with mouse monoclonal antibodies recognizing the extracellular domain of the EGFR molecule. The catalyzed product was visualized with 3,3'-diaminobenzidine Chromogen Kit and lightly counterstained with Mayer's hematoxylin. Quantitative EGFR immunohistochemistry (IHC) was done with SAMBA 4000 Cell Image Analysis System, without knowledge of the clinical outcome, to yield mean absorbance (MOD), staining index (SI), and quick score (QS). These EGFR IHC parameters were correlated with the T stage, N stage, combined stage grouping, and recursive partitioning analysis classes. Subsequently, the EGFR parameters were correlated with the outcome end points, i.e., overall survival (OS), disease-free survival (DFS), local-regional (LR) relapse, and distant metastasis rates. We found that HNSCCs exhibited a wide variation in EGFR expression (MOD, 0.2-66.0; SI, 0.3-97.0; QS, 0.01-69.9) with a relatively strong but nonlinear correlation between MOD and SI (r = 0.79). There was no correlation between EGFR expression and T stage, N stage, stage grouping, and recursive partitioning analysis classes (r = -0.07 to 0.17). The OS and DFS rates of patients with high EGFR-expressing HNSCCs (>median MOD) were highly significantly lower (P = 0.0006 and P = 0.0016, respectively) and the LR relapse rate was highly significantly higher (P = 0.0031) compared with those of patients with low EGFR-expressing HNSCCs. However, there was no difference in the distant metastasis rate between the two groups (P = 0.96). Significant correlations, although somewhat less robust than MOD, were also observed between SI and QS and the OS, DFS, and LR relapse rates. Multivariate analysis showed that EGFR expression was an independent determinant of survival and a robust independent predictor of LR relapse. In summary, this correlative study in a large series of patients revealed that EGFR expression, which varied considerably among HNSCCs, was a strong independent prognostic indicator for OS and DFS and a robust predictor for LR relapse but not for distant metastasis. The data suggest that EGFR IHC should be considered for selecting patients for more aggressive combined therapies or enrollment into trials targeting EGFR signaling pathways.

P105 as a prognostic indicator in patients irradiated for locally advanced head-and-neck cancer: a clinical/laboratory correlative analysis of RTOG-9003.

PURPOSE: In a previous retrospective study, p105 AD, a proliferation-associated nuclear antigen density (AD), was found to be an independent prognostic factor for patients irradiated for locally advanced head-and-neck cancer. We sought to confirm this finding by analyzing patients entered on RTOG 9003, a Phase III randomized trial of altered fractionation radiotherapy. METHODS AND MATERIALS: Paraffin blocks of pretreatment biopsies of the primary tumor of patients with Stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, or supraglottic larynx, or Stage II squamous cell carcinoma of the hypopharynx or base of tongue entered on RTOG 9003 were prospectively collected at patient entry. From these paraffin blocks, areas of tumor were selected based on histologic examinations and sectioned. Nuclear suspensions were then prepared and processed for p105 antibody and DNA staining. Flow cytometric quantification of p105 labeling indices and DNA content were then performed for correlation with local-regional control and survival. RESULTS: Paraffin blocks of tumor biopsies from 457 of 1073 patients entered were available for p105 determination. There was no significant difference in pretreatment characteristics between patients who had paraffin blocks available or not available. The median (range) of p105 labeling index (LI-C), p105 labeling index of cells in S phase (p105 LI-S), and p105 AD were 56 (range: 6-99), 8.255 (range: 0.913-23), and 67 (range: 5-364), respectively. Multivariate analysis of prognostic factors showed that T stage, N stage, Karnofsky performance status, and fractionation schedule were significant for local-regional control (p < 0.0001, 0.0011, <0.0001, and 0.007, respectively) and T stage, N stage, Karnofsky performance status, and tumor grade were significant for survival (p = 0.018, 0.002, <0.0001, and 0.0058, respectively). Neither p105 LI-C nor p105 LI-S nor p105 AD nor DNA ploidy was significant for local-regional control or survival. CONCLUSION: p105 labeling indices, antigen density, and DNA ploidy do not predict the outcome of patients irradiated for advanced squamous cell carcinomas of the head and neck.

Recursive partitioning analysis of pretreatment variables of 416 patients with locoregional esophageal cancer treated with definitive concomitant chemoradiotherapy on Intergroup and Radiation Therapy Oncology Group trials.

PURPOSE: To analyze the relative contributions of uniformly collected pretreatment patient- and tumor-related variables to survival and to identify the terminal nodes via recursive partitioning analysis (RPA) that could be used as a stratification variable for future Phase III trials. METHODS AND MATERIALS: From two Intergroup trials (85-01, n = 130; and 94-05, n = 218) and one Radiation Therapy Oncology Group trial (92-07, n = 68), we identified 416 patients who were treated with definitive concomitant cisplatin and 5-FU-based chemoradiotherapy and analyzed their data for survival by RPA to define prognostic classes. The following pretreatment factors were evaluated: histologic type, age, weight loss, Karnofsky performance status, gender, race, T stage, tumor location, tumor size, N stage, and degree of dysphagia. The entire data set was considered as the initial node. The criterion for split points was the smallest p value less than unadjusted 0.05. RESULTS: Of the 416 patients, 336 (81%) were dead at the time of the analysis. The RPA identified only one significant split: pretreatment weight loss in the prior 6 months of <10% vs. > or =10%. After adjusting for multiple comparisons, no other split approached statistical significance. CONCLUSION: Unlike our experience with malignant glioma, brain metastases, and locally advanced non-small-cell lung cancer, RPA failed to identify novel prognostic information that could be incorporated into the stratification scheme of future chemoradiotherapy trials for esophageal cancer. Furthermore, our analysis validated the percentage of weight loss as a stratification variable for esophageal cancer.

Outcome of salvage total laryngectomy following organ preservation therapy: the Radiation Therapy Oncology Group trial 91-11.

OBJECTIVE: To evaluate the incidence of morbidity, mortality, and disease control for patients requiring salvage total laryngectomy (TL) following organ preservation therapy. DESIGN: Patients entered into a 3-arm randomized prospective multi-institutional trial for laryngeal preservation who required TL following initial treatment. SETTING: The Radiation Therapy Oncology Group 91-11 trial for laryngeal preservation. PATIENTS: From 1992 to 2000, 517 evaluable patients were randomized to receive chemotherapy followed by radiation therapy (arm 1), concomitant chemotherapy and radiation therapy (arm 2), or radiation therapy alone (arm 3). RESULTS: Overall, TL was required in 129 patients. The incidence was 28%, 16%, and 31% in arms 1, 2, and 3, respectively (P =.002). Of these, 7 patients (5%) required TL for aspiration or necrosis. Following TL, the incidence of major and minor complications ranged from 52% to 59% and did not differ significantly among the 3 arms. Pharyngocutaneous fistula was lowest in arm 3 (15%) and highest in arm 2 (30%) (P>.05). There was 1 perioperative death. Local-regional control following salvage TL was 74% for arms 1 and 2 and 90% for arm 3. At 24 months, the overall survival was 69% (arm 1), 71% (arm 2), and 76% (arm 3) (P>.73). CONCLUSIONS: Laryngectomy following organ preservation treatment is associated with acceptable morbidity. Perioperative mortality is low but up to one third of patients will develop a pharyngocutaneous fistula. Local-regional control is excellent for this group of patients. Survival following salvage TL was not influenced by the initial organ preservation treatment.

Impact of nutrition support on treatment outcome in patients with locally advanced head and neck squamous cell cancer treated with definitive radiotherapy: a secondary analysis of RTOG trial 90-03.

BACKGROUND: The aim was to evaluate the relationship between nutrition support (NS) on host toxicity and cancer outcome in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing definitive radiotherapy (XRT). METHODS: We performed a secondary analysis of Radiation Therapy Oncology Group (RTOG) 90-03, a prospective randomized trial evaluating four definitive XRT fractionation schedules in patients with locally advanced HNSCC, which prospectively collected data on NS delivered before treatment (BNS), during treatment (TNS), and after definitive XRT. NS data and pretreatment characteristics of the 1073 evaluable patients were analyzed against therapy toxicity and outcome. RESULTS: Patients receiving BNS experienced significantly less weight loss by the end of treatment and less grade 3 to 4 mucositis than patients not receiving BNS. However, patients receiving BNS had a poorer 5-year actuarial locoregional control rate than patients receiving TNS or no NS (29%, 55%, and 57%, respectively, p < .0001) and a poorer 5-year overall survival rate (16%, 36%, and 49%, respectively, p < .0001). Patients receiving BNS were significantly more likely to have a higher T classification, N status, and overall American Joint Committee on Cancer (AJCC) stage and initial presentation with greater pretreatment weight loss, and a poorer Karnofsky Performance Status (KPS) than patients not receiving BNS. After adjusting for the impact of these prognostic factors through a recursive partition analysis, a multivariate analysis with a stratified Cox model found that BNS was still a highly significant independent prognostic factor for increased locoregional failure (hazards ratio [HR], 1.47; 95% confidence interval [CI], 1.21-1.79; p < .0001) and death (HR, 1.41; 95% CI, 1.19-1.67; p < .0001). CONCLUSION: In this study, the largest prospective evaluation of nutrition data in treated patients with cancer, BNS was associated with inferior treatment outcome in the patients with HNSCC undergoing XRT. These results should be considered hypothesis generating and encourage prospective clinical research and identification of the mechanisms underlying this finding.

Influence of number of CAG repeats on local control in the RTOG 86-10 protocol.

OBJECTIVES: The number of CAG repeats on the androgen receptor (AR) gene is inversely proportional to transcriptional activity. The purpose of this study was to determine if short-term androgen deprivation therapy (RT + HT) can improve outcome in patients with tumors with short CAG repeats (<19). MATERIALS AND METHODS: Prostate cancer patients were randomized to receive either radiotherapy (RT) alone or (RT + HT) in the RTOG 86-10 study. CAG repeats were measured in 94 tumor specimens (21%; test cohort) of the 456 (parent cohort) analyzable cases. AR flow cytometry measurements were done on 13 patients. The effect on local failure (LF), distant metastases (DM), prostate cancer survival (PSS), and overall survival (OS) was studied. RESULTS: Pretreatment characteristics and assigned treatment arm were not significantly different between the parent and test groups except for a significantly higher risk of death (P = 0.049) in the test group. The median CAG repeat was 19. There were no significant differences in stage, or Gleason score between high (19 or greater) and low CAG (<19) patients within each treatment group. Number of CAG repeats alone did not significantly influence LF, DM, PSS, and OS. However, when the CAG repeat outcome was studied in conjunction with androgen deprivation therapy, patients with CAG <19 who received H + RT had improved local control as compared with patients who received RT alone (P = 0.026, 5-year rates 4.6% versus 36.4%) and improved local control over patients with CAG > or =19 that received H + RT (P = 0.028). CONCLUSIONS: Patients with short CAG repeats show a local control benefit with short-term androgen deprivation therapy, but no improvement in survival.

Effect of education level on outcome of patients treated on Radiation Therapy Oncology Group Protocol 90-03.

BACKGROUND: It has been hypothesized that people in lower socioeconomic groups have worse outcomes because they present with advanced-stage cancers or receive inadequate treatment. The authors investigated this hypothesis by using education level as a proxy for socioeconomic status in patients treated on Radiation Therapy Oncology Group (RTOG) Protocol 90-03. METHODS: RTOG 90-03 was a Phase III randomized trial investigating four different radiation fractionation schedules in the treatment of locally advanced head and neck carcinomas. Overall survival and locoregional control rates were analyzed by education level as measured by patient response on the demographic form at study entry. RESULTS: A significant difference was observed in the distribution of patients by education level between the standard fractionated radiation treatment arm and the hyperfractionated radiation treatment arm. More patients in the standard fractionated treatment arm had a higher education level (P = 0.018). Patients attending college had highly and significantly better overall survival and locoregional control than the other groups combined (P = 0.0056 and P = 0.025, respectively: from Cox proportional hazards models stratified by assigned treatment with educational level, T classification, N classification, Karnofsky performance status, primary site, and race). Multivariate analysis revealed that education level was significant for predicting both overall survival and locoregional control when comparing attended college/technical school compared with all other education levels. CONCLUSIONS: Patients attending college or technical school had improved overall survival and locoregional control. These differences cannot be explained by differences in tumor stage or treatment. Poorer overall health or lack of support systems contributing to these results needs to be investigated further.