Double-blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer: Long-term follow-up of a trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590).

BACKGROUND: 13-Cis retinoic acid (13-CRA) is a synthetic vitamin A derivative. High-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long-term results from a phase 3 randomized trial that compared treatment with low-dose 13-CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS). METHODS: In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low-dose 13-CRA (weight-based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing-risk approach and the log-rank test were used to compare the time to SPT and OS, respectively, between groups. RESULTS: 13-CRA neither significantly reduced the cumulative incidence of SPT (P = .61) nor improved the time to SPT (hazard ratio [HR] for 13-CRA/placebo; 0.86; P = .61). Despite limited power, there was a trend toward improved OS for the 13-CRA arm (HR, 0.75; P = .14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50; P = .057) and among women (N = 39; HR, 0.44; P = .065) and never/former smokers (N = 129; HR, 0.61; P = .055), with a median follow-up of 16 years. The main 13-CRA related toxicities were dry skin and cheilitis. CONCLUSIONS: Treatment with low-dose 13-CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials. Cancer 2017;123:4653-4662. © 2017 American Cancer Society.

Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM.

Irinotecan has radiosensitizing effects and shows synergism with nitrosoureas. We performed a Phase II study of RT and irinotecan, followed by BCNU plus irinotecan in newly-diagnosed GBM. The MTD for patients receiving enzyme-inducing anticonvulsants (EIAC) was as follows: irinotecan 400 mg/m(2)/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m(2) Day 1, and irinotecan, 400 mg/m(2) on Days 1, 8, 22 and 29, every 6 weeks. The MTD for non-EIAC patients was as follows: irinotecan 125 mg/m(2)/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m(2) Day 1 and irinotecan 75 mg/m(2) Days 1, 8, 22 and 29, every 6 weeks. Median OS was 10.8 mos. (95% CI: 7.7-14.9); OS at 12 months was 44.6% (95% CI: 33.3-59.8) and PFS 6 was 28.6% (95% CI: 18.9-43.2). Patients went off treatment due to adverse events (7%), refusal (11%), progressive disease (48%), death (9%), and other (9%); 16% completed protocol treatment. Survival was similar in patients with variant (6/7 or 7/7) and wild-type (6/6) UGT1A1*28 genotypic alleles. Grade 3-4 toxicity was more common in non-EIAC patients with variant alleles. SN-38 C(max) and AUC in EIAC patients receiving 400 mg/m(2) irinotecan were 20.9 ng/ml and 212 ng/ml h, and in non-EIAC patients receiving 125 mg/m(2), 15.5 ng/ml and 207 ng/ml h. SN-38 AUC varied by UGT1A1*28 status in non-EIAC patients. This regimen was not significantly active and radiosensitization was not observed. Non-EIAC patients with UGT1A1*28 variant alleles appear particularly sensitive to toxicity from irinotecan.

A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma.

Combined deletion of chromosomes 1p and 19q is associated with improved prognosis and responsiveness to therapy in patients with anaplastic oligodendroglioma. The deletions usually involve whole chromosome arms, suggesting a t(1;19)(q10;p10). Using stem cell medium, we cultured a few tumors. Paraffin-embedded tissue was obtained from 21 Mayo Clinic patients and 98 patients enrolled in 2 North Central Cancer Treatment Group (NCCTG) low-grade glioma trials. Interphase fusion of CEP1 and 19p12 probes detected the t(1;19). 1p/19q deletions were evaluated by fluorescence in situ hybridization. Upon culture, one oligodendroglioma contained an unbalanced 45,XX,t(1;19)(q10;p10). CEP1/19p12 fusion was observed in all metaphases and 74% of interphase nuclei. Among Mayo Clinic oligodendrogliomas, the prevalence of fusion was 81%. Among NCCTG patients, CEP1/19p12 fusion prevalence was 55%, 47%, and 0% among the oligodendrogliomas, mixed oligoastrocytomas, and astrocytomas, respectively. Ninety-one percent of NCCTG gliomas with 1p/19q deletion and 12% without 1p/19q deletion had CEP1/19p12 fusion (P < 0.001, chi(2) test). The median overall survival (OS) for all patients was 8.1 years without fusion and 11.9 years with fusion (P = 0.003). The median OS for patients with low-grade oligodendroglioma was 9.1 years without fusion and 13.0 years with fusion (P = 0.01). Similar significant median OS differences were observed for patients with combined 1p/19q deletions. The absence of alterations was associated with a significantly shorter OS for patients who received higher doses of radiotherapy. Our results strongly suggest that a t(1;19)(q10;p10) mediates the combined 1p/19q deletion in human gliomas. Like combined 1p/19q deletion, the 1;19 translocation is associated with superior OS and progression-free survival in low-grade glioma patients.

Effects of radiotherapy on cognitive function in patients with low-grade glioma measured by the folstein mini-mental state examination.

PURPOSE: To assess the neurocognitive effects of cranial radiotherapy on patients with low-grade gliomas, we analyzed cognitive performance data collected in a prospective, intergroup clinical trial. METHODS: Patients included 203 adults with supratentorial low-grade gliomas randomly assigned to a lower dose (50.4 Gy in 28 fractions) or a higher dose (64.8 Gy in 36 fractions) of localized radiotherapy. Folstein Mini-Mental State Examination (MMSE) scores and neurologic function scores (NFS) at baseline and key evaluations were analyzed. Median follow-up was 7.4 years in 101 patients still alive. A change of more than three MMSE points was considered clinically significant. RESULTS: In patients without tumor progression, significant deterioration from baseline occurred at years 1, 2, and 5 in 8.2%, 4.6%, and 5.3% of patients, respectively. Most patients with an abnormal baseline MMSE score (< 27) experienced significant increases. Baseline variables such as radiation dose, conformal versus conventional radiotherapy, number of radiation fields, age, sex, tumor size, NFS, seizures, and seizure medications did not predict cognitive function changes. CONCLUSION: In this population, most low-grade glioma patients maintained a stable neurocognitive status after focal radiotherapy as measured by the MMSE. Patients with an abnormal baseline MMSE were more likely to have an improvement in cognitive abilities than deterioration after receiving radiotherapy. Only a small percentage of patients had cognitive deterioration after radiotherapy. However, more discriminating neurocognitive assessment tools may identify cognitive decline not apparent with the use of the MMSE.

Cognitive function after radiotherapy for supratentorial low-grade glioma: a North Central Cancer Treatment Group prospective study.

PURPOSE: To evaluate the effects of cranial radiotherapy (RT) on cognitive function in patients with supratentorial low-grade glioma. METHODS AND MATERIALS: Twenty adult patients with supratentorial low-grade glioma were treated with 50.4 Gy (10 patients) or 64.8 Gy (10 patients) localized RT. The patients then were evaluated with an extensive battery of psychometric tests at baseline (before RT) and at approximately 18-month intervals for as long as 5 years after completing RT. To allow patients to serve as their own controls, cognitive performance was evaluated as change in scores over time. All patients underwent at least two evaluations. RESULTS: Baseline test scores were below average compared with age-specific norms. At the second evaluation, the groups' mean test scores were higher than their initial performances on all psychometric measures, although the improvement was not statistically significant. No changes in cognitive performance were seen during the evaluation period when test scores were analyzed by age, treatment, tumor location, tumor type, or extent of resection. CONCLUSIONS: Cognitive function was stable after RT in these patients evaluated prospectively during 3 years of follow-up. Slight improvements in some cognitive areas are consistent with practice effects attributable to increased familiarity with test procedures and content.

Adult patients with supratentorial pilocytic astrocytomas: a prospective multicenter clinical trial.

PURPOSE: Supratentorial pilocytic astrocytomas in adults are uncommon. A prospective clinical trial was conducted to obtain clinical and outcome data in these patients. METHODS AND MATERIALS: Between 1986 and 1994, 20 eligible adults with supratentorial pilocytic astrocytomas were enrolled in a prospective intergroup trial of radiotherapy (RT) after biopsy (3 patients) or observation after gross (11 patients) or subtotal (6 patients) resection. RESULTS: At the time of analysis (median follow-up, 10 years), 1 patient (5%) had died and 19 patients (95%) were alive. The 5-year progression-free and overall survival rates were 95%. The cause of death in the patient who died (2.1 years after enrollment) was unknown; a radiographic examination obtained shortly before the patient's demise revealed no signs of progression. Progression in 1 patient approximately 1 month after enrollment required injection of (32)P into an enlarging cyst. The patient required RT approximately 18 months later because of further progression. This patient was alive without evidence of progression 9 years after RT. No toxic effects had been recorded at the latest follow-up examinations. CONCLUSION: With follow-up comparable or superior to that in many retrospective studies, the results of this prospective trial confirm that adults with pilocytic astrocytomas have a favorable prognosis with regard to survival and neurologic function. The vast majority of patients remained stable after gross or subtotal resection and no adjuvant therapy. RT need not be offered to adults with supratentorial pilocytic astrocytoma after gross or subtotal resection; instead, close observation is recommended. Because only 3 patients received RT after biopsy, it is difficult to comment on the effect of RT on their outcome as a group.

Importance of baseline mini-mental state examination as a prognostic factor for patients with low-grade glioma.

PURPOSE: The outcome and cognitive performance data collected in a prospective, intergroup clinical trial were analyzed to assess the prognostic importance of the baseline (before radiotherapy) Mini-Mental State Examination (MMSE) score in patients with low-grade glioma. METHODS AND MATERIALS: The patients studied were 203 adults with a supratentorial low-grade glioma randomly assigned to low-dose (50.4 Gy in 28 fractions) or high-dose (64.8 Gy in 36 fractions) localized radiotherapy. Folstein MMSE scores and neurologic function scores at baseline in combination with multiple other baseline variables were analyzed. The median follow-up was 7.4 years for the 101 patients still alive. RESULTS: Patients (n = 36) with an abnormal baseline MMSE score (< or =26) had a worse 5-year progression-free survival rate (27% vs. 60%; p <0.001) and overall survival rate (31% vs. 76%; p <0.001) compared with those with a normal score. On multivariate analysis, the baseline MMSE score was a statistically significant predictor of survival. Other factors associated with overall survival were age, tumor size, and tumor histologic type. CONCLUSION: The presence of an abnormal baseline MMSE score was a strong predictor of poorer progression-free and overall survival for patients with a low-grade glioma. The baseline MMSE should be considered in future prognostic scoring systems.

Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer.

PURPOSE: This Phase III study was performed to determine whether twice-daily (b.i.d.) radiotherapy (RT) resulted in better survival than once-daily (q.d.) RT for patients with limited-stage small-cell lung cancer (LD-SCLC). METHODS AND MATERIALS: A total of 310 patients with LD-SCLC initially received three cycles of etoposide and cisplatin. Subsequently, the 261 patients without significant progression were randomized to two cycles of etoposide and cisplatin plus either q.d. RT (50.4 Gy in 28 fractions) or split-course b.i.d. RT (24 Gy in 16 fractions, a 2.5-week break, and 24 Gy in 16 fractions) to the chest. Patients then received a sixth cycle of etoposide and cisplatin followed by prophylactic cranial RT. RESULTS: Follow-up ranged from 4.6 to 11.9 years (median, 7.4 years). The median survival and 5-year survival rate from randomization was 20.6 months and 21% for patients who received q.d. RT compared with 20.6 months and 22% for those who received b.i.d. RT (p = 0.68), respectively. No statistically significant differences were found in the rates of progression (p = 0.68), intrathoracic failure (p = 0.45), in-field failure (p = 0.62), or distant failure (p = 0.82) between the two treatment arms. No statistically significant difference was found in the overall rate of Grade 3 or worse (p = 0.83) or Grade 4 or worse toxicity (p = 0.95). Grade 3 or worse esophagitis (p = 0.05) was more common in the b.i.d. arm. Grade 5 toxicity occurred in 4 (3%) of 130 patients who received b.i.d. RT compared with 0 (0%) of 131 who received q.d. RT (p = 0.04). CONCLUSION: Although this study did not demonstrate an advantage to split-course b.i.d. RT, the long-term survival was favorable, likely reflecting the positive influences of concurrent combined modality therapy and prophylactic cranial RT.

Validation of EORTC prognostic factors for adults with low-grade glioma: a report using intergroup 86-72-51.

PURPOSE: A prognostic index for survival was constructed and validated from patient data from two European Organisation for Research and Treatment of Cancer (EORTC) radiation trials for low-grade glioma (LGG). We sought to independently validate this prognostic index with a separate prospectively collected data set (Intergroup 86-72-51). METHODS AND MATERIALS: Two hundred three patients were treated in a North Central Cancer Treatment Group-led trial that randomized patients with supratentorial LGG to 50.4 or 64.8 Gy. Risk factors from the EORTC prognostic index were analyzed for prognostic value: histology, tumor size, neurologic deficit, age, and tumor crossing the midline. The high-risk group was defined as patients with more than two risk factors. In addition, the Mini Mental Status Examination (MMSE) score, extent of surgical resection, and 1p19q status were also analyzed for prognostic value. RESULTS: On univariate analysis, the following were statistically significant (p<0.05) detrimental factors for both progression-free survival (PFS) and overall survival (OS): astrocytoma histology, tumor size, and less than total resection. A Mini Mental Status Examination score of more than 26 was a favorable prognostic factor. Multivariate analysis showed that tumor size and MMSE score were significant predictors of OS whereas tumor size, astrocytoma histology, and MMSE score were significant predictors of PFS. Analyzing by the EORTC risk groups, we found that the low-risk group had significantly better median OS (10.8 years vs. 3.9 years, p<0.0001) and PFS (6.2 years vs. 1.9 years, p<0.0001) than the high-risk group. The 1p19q status was available in 66 patients. Co-deletion of 1p19q was a favorable prognostic factor for OS vs. one or no deletion (median OS, 12.6 years vs. 7.2 years; p=0.03). CONCLUSIONS: Although the low-risk group as defined by EORTC criteria had a superior PFS and OS to the high-risk group, this is primarily because of the influence of histology and tumor size. Co-deletion of 1p19q is a prognostic factor. Future studies are needed to develop a more refined prognostic system that combines clinical prognostic features with more robust molecular and genetic data.

A prospective study of quality of life in adults with newly diagnosed high-grade gliomas: comparison of patient and caregiver ratings of quality of life.

OBJECTIVE: To examine whether a caregiver can provide reliable proxy quality of life (QOL) ratings of their adult significant other with a newly diagnosed high-grade glioma. METHODS: This prospective QOL study was a companion protocol for 3 phase II high-grade glioma protocols. At study entry, 2 months, and 4 months after enrollment, 5 self-administered forms were completed by 197 patients and their caregivers to assess QOL. RESULTS: Caregiver ratings of QOL were available, respectively, for 92%, 93%, and 88% of baseline, 1st, and 2nd subsequent follow-up evaluations of patients who had completed their QOL assessments. There was a strong relationship between patient and caregiver QOL scores (Spearman and intraclass correlation coefficients greater than 0.5 for 87% and 80% of the measurements, respectively); however, for some measures (eg, the profiles of mood states short form) there was better agreement between patient and caregiver scores when the QOL scores were higher. There was good agreement between patient and proxy ratings independent of the cognitive function of the patient, except for the profiles of mood states short form with better correlation between patients and caregivers for those patients without cognitive impairment. CONCLUSIONS: In this multi-institutional prospective study there is a strong correlation between high-grade glioma patient and caregiver QOL scores, although for some measures this correlation is stronger for those patients without cognitive impairment. To improve the acquisition and the accuracy of assessing QOL status in high-grade glioma patients, proxy ratings from caregivers should also be obtained in conjunction with the patient, and consideration be given to substituting proxy ratings when a patient's self-report is absent.

Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177.

PURPOSE: Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial. PATIENTS AND METHODS: Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m(2) daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m(2) daily for 5 days every 28 days). The primary end point was survival at 1 year. RESULTS: Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival. CONCLUSION: Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.

Prospective study of quality of life in adults with newly diagnosed high-grade gliomas.

OBJECTIVE: To assess baseline quality of life (QOL) and its prognostic importance for adults with newly diagnosed high-grade gliomas, we analyzed QOL and outcome data prospectively collected in three phase II high-grade glioma protocols. METHODS: At study entry, patients completed five self-administered forms to assess overall QOL (linear analogue scale assessment [LASA] and Functional Assessment of Cancer Therapy-Brain [FACT-Br]); fatigue (Symptom Distress Scale [SDS]); excessive daytime somnolence (Epworth Sleepiness Scale [ESS]); and depression (POMS-SF). Folstein Mini-Mental State Examination (MMSE) and Eastern Cooperative Oncology Group (ECOG) performance scores (PS) were obtained by the health care provider. RESULTS: Baseline QOL data were available for 194 of 220 patients (88%) enrolled in the three protocols. Differences in baseline QOL among the three studies were not statistically significant. One-third of patients had clinically significant fatigue at baseline. Increased fatigue (P = 0.003), excessive daytime somnolence (P = 0.01), and lower overall QOL scores (LASA, P = 0.001; FACT-Br, P = 0.0001) correlated with worse ECOG PS. No relation was found between QOL and corticosteroid or anticonvulsant therapy, extent of resection, tumor grade, or sex. Multivariate analyses found worse ECOG PS (PS 2, P = 0.007) associated with increased fatigue. Worse ECOG PS (PS 2, P = 0.002) was also associated with worse overall QOL (LASA). On multivariate analyses of survival, increased fatigue (P = 0.003) predicted poorer overall survival. CONCLUSIONS: Performance status is related to QOL in patients with newly diagnosed high-grade brain tumors. Increased fatigue is an independent predictor of overall survival. Interventional studies directed at improving QOL, especially fatigue, may have important benefits for these patients.

A prospective study of quality of life in adults with newly diagnosed high-grade gliomas: the impact of the extent of resection on quality of life and survival.

OBJECTIVE: To describe the quality of life (QOL) over time for adults with newly diagnosed high-grade gliomas and to examine the relationship between QOL and outcome data collected in three prospective cooperative group clinical trials. METHODS: The QOL study was a companion protocol for three Phase II high-grade glioma protocols. Five self-administered forms were completed by patients to assess QOL at study entry, 2 months, and 4 months after enrollment. RESULTS: QOL data were available for baseline, first, and second subsequent follow-up evaluations for 89%, 71%, and 69% of patients, respectively. A significant proportion of patients (47.1%) experienced impaired QOL (QOL < or = 50) in at least one measure at subsequent evaluations, whereas most patients (88%) with impaired QOL at baseline continued to have impaired QOL at subsequent evaluations. On multivariable analyses, baseline QOL measures were predictive of QOL at the time of follow-up. In addition, patients who underwent a gross total resection were much less likely to have impaired QOL (P = 0.006), were less likely to experience worsening depression (P = 0.0008), and were more likely to have improved QOL (P = 0.003) at their first follow-up evaluation. Changes in QOL measures over time were not found to be associated with survival in multivariable analyses that adjusted for known prognostic variables; variables that were independently associated with improved survival were better performance status (P < 0.001), younger age (P < 0.001), and greater extent of resection (P < 0.001). CONCLUSION: Baseline QOL was predictive of QOL over time. Gross total resection was associated with longer survival and improved QOL over time for patients with high-grade gliomas.