Glenn Bauman

Preservation of Memory With Conformal Avoidance of the Hippocampal Neural Stem-Cell Compartment During Whole-Brain Radiotherapy for Brain Metastases (RTOG 0933): A Phase II Multi-Institutional Trial

PURPOSE Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Intensity-modulated radiotherapy can be used to avoid conformally the hippocampal neural stem-cell compartment during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with prespecified comparison with a historical control of patients treated with WBRT without hippocampal avoidance. PATIENTS AND METHODS Eligible adult patients with brain metastases received HA-WBRT to 30 Gy in 10 fractions. Standardized cognitive function and quality-of-life (QOL) assessments were performed at baseline and 2, 4, and 6 months. The primary end point was the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) at 4 months. The historical control demonstrated a 30% mean relative decline in HVLT-R DR from baseline to 4 months. To detect a mean relative decline ≤ 15% in HVLT-R DR after HA-WBRT, 51 analyzable patients were required to ensure 80% statistical power with α = 0.05. RESULTS Of 113 patients accrued from March 2011 through November 2012, 42 patients were analyzable at 4 months. Mean relative decline in HVLT-R DR from baseline to 4 months was 7.0% (95% CI, -4.7% to 18.7%), significantly lower in comparison with the historical control (P < .001). No decline in QOL scores was observed. Two grade 3 toxicities and no grade 4 to 5 toxicities were reported. Median survival was 6.8 months. CONCLUSION Conformal avoidance of the hippocampus during WBRT is associated with preservation of memory and QOL as compared with historical series.

Supratentorial low-grade glioma in adults: an analysis of prognostic factors and timing of radiation.

PURPOSE To review the outcomes of patients with low-grade glioma diagnosed by modern imaging and treated at a center where postponing radiotherapy was common practice. METHODS We reviewed the records of patients (age > or = 18 years) with pathologically confirmed supratentorial low-grade fibrillary astrocytoma, oligodendroglioma, and mixed glioma treated at a regional cancer center in Canada between 1979 and 1995. RESULTS Median survival for the entire group (N = 167; mean age 40.6 years) was 10.5 years with 5- and 10-year survival rates of 72% and 50%, respectively. Median progression-free survival was 4.9 years with 5- and 10-year progression-free rates of 50% and 12%, respectively. Overall and progression-free survivals were longer for patients with an oligodendroglioma or mixed glioma than with astrocytoma (median 13 v 7.5 years, P = .003; progression-free 5.6 v 4.4 years, p = .054). Age at diagnosis < or = 40 years, seizures at presentation, minimal residual tumor after surgery, Karnofsky performance status > or = 70, and oligodendroglioma or mixed glioma pathology were associated with significantly longer median survival on univariate and multivariate analyses. Radiotherapy deferred until tumor progression (v immediate radiotherapy) was associated with longer survival on univariate analysis, but an imbalance in other variables accounted for this advantage such that timing of radiotherapy was not an independent (favorable or adverse) prognostic factor on multivariate analysis. CONCLUSION Patients with low-grade glioma diagnosed by modern imaging can be expected to live a long time; timing of radiotherapy may be a less important determinant of survival than nontreatment variables and residual tumor bulk.

Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas

INTRODUCTION Allelic loss of the short arm of chromosome 1 predicts radiographic response to chemotherapy and long overall survival times in patients with anaplastic oligodendrogliomas. Using a database of patients with oligodendrogliomas in whom chromosome 1p status was known, we explored whether allelic loss of 1p also predicted longer duration of tumor control when radiotherapy was part of the initial treatment of these patients. MATERIALS AND METHODS We measured progression-free survival following radiotherapy in a cohort of patients with World Health Organization (WHO) Grade II and WHO Grade III oligodendrogliomas. The effects on progression-free survival of patient age, Karnofsky performance score (KPS), tumor grade when irradiated and chromosome 1p status were examined by univariate and multivariate statistical analyses. For the subset of patients with newly diagnosed anaplastic oligodendrogliomas, relationships between use of chemotherapy, chromosome 1p status and progression-free survival were also examined. RESULTS Fifty-five patients (29 male, 26 female; ages 18-75 years; median, 44 years; KPS 50-90, median 80) were irradiated for either a WHO Grade II (n = 19) or Grade III (n = 36) oligodendroglioma. Twenty-eight patients had chemotherapy immediately prior to radiotherapy, and 27 had chemotherapy at progression following radiotherapy. The median radiation dose was 54 Gy in 30 fractions. Loss of heterozygosity (LOH) at chromosome 1p was evident in 36 tumors and absent in 19. Overall median progression-free survival after radiotherapy was 40.4 months. Median progression-free survival was 55.0 months for patients whose tumors harbored 1p loss vs. 6.2 months for those patients whose tumors retained both copies of chromosome 1p (p < 0.001). On both univariate and multivariate analyses, chromosome lp loss was the principal independent predictor of longer progression-free survival for patients with Grade II and III oligodendrogliomas. For Grade III oligodendrogliomas, chemotherapy as an adjunct to radiotherapy prolonged tumor control for those patients whose tumors harbored allelic loss of chromosome 1p (p = 0.004). CONCLUSION These data suggest allelic loss of chromosome 1p in patients with oligodendroglial neoplasms predicts longer progression-free survival among patients receiving radiotherapy +/- chemotherapy as part of their initial treatment. Chromosome 1p loss may be an important stratification variable in future therapeutic trials of oligodendroglioma.

Pretreatment factors predict overall survival for patients with low-grade glioma : A recursive partitioning analysis

PURPOSE Three databases were pooled and analyzed to determine which groupings of prognostic factors best predicted overall survival for patients with low-grade gliomas treated with surgery and immediate or delayed radiotherapy. METHODS AND MATERIALS Databases of patients with low-grade gliomas compiled at the London Regional Cancer Centre (LRCC), the Norwegian Radium Hospital (NRH), and the University of California, San Francisco (UCSF) were merged. Inclusion criteria for the pooled analysis included: age > or =18 years and histologically confirmed low-grade (World Health Organization Grade II) supratentorial fibrillary astrocytoma, oligodendroglioma or mixed oligoastrocytoma. Factors analyzed for prognostic significance included: age at diagnosis, gender, seizures at presentation, presence of enhancement on computed tomography (CT) or magnetic resonance imaging (MRI), Karnofsky Performance Status (KPS) at diagnosis, histology, extent of surgical resection, timing of radiotherapy, and treating institution. Univariate and multivariate analysis of overall survival for these factors was performed. Recursive partitioning was performed to generate prognostic groups using these factors. RESULTS From the combined databases, 401 patients were eligible for analysis. Median survival for the entire group was 95 months/7.9 years. On univariate analysis age 18-40, presence of seizures at presentation, KPS > or =70, treating institution, and absence of contrast enhancement were associated with improved overall survival. On multivariate analysis, these factors remained independent predictors of improved overall survival. Recursive partitioning analysis yielded four prognostic groups with statistically different median survivals (MS): Group I (n = 41: KPS <70, age >40) MS 12 months; Group II (n = 34: KPS > or =70, age >40, enhancement present) MS 46 months; Group III (n = 138: KPS <70, age 18-40 or KPS > or =70 age >40, no enhancement) MS 87 months; Group IV (n = 188: KPS > or =70, age 18-40) MS 128 months. CONCLUSION Clusters of pretreatment prognostic factors described subgroups of low-grade glioma patients with divergent overall survivals. Consideration of these prognostic subgroups may be important when considering timing of interventions for these patients and in the stratification of patients for clinical trials.

Tracking the dose distribution in radiation therapy by accounting for variable anatomy

The goal of this research is to calculate the daily and cumulative dose distribution received by the radiotherapy patient while accounting for variable anatomy, by tracking the dose distribution delivered to tissue elements (voxels) that move within the patient. Non-linear image registration techniques (i.e., thin-plate splines) are used along with a conventional treatment planning system to combine the dose distributions computed for each 3D computed tomography (CT) study taken during treatment. For a clinical prostate case, we demonstrate that there are significant localized dose differences due to systematic voxel motion in a single fraction as well as in 15 cumulative fractions. The largest positive dose differences in rectum, bladder and seminal vesicles were 29%, 2% and 24%, respectively, after the first fraction of radiation treatment compared to the planned dose. After 15 cumulative fractions, the largest positive dose differences in rectum, bladder and seminal vesicles were 23%, 32% and 18%, respectively, compared to the planned dose. A sensitivity analysis of control point placement is also presented. This method provides an important understanding of actual delivered doses and has the potential to provide quantitative information to use as a guide for adaptive radiation treatments.

A prospective study of short-course radiotherapy in poor prognosis glioblastoma multiforme

PURPOSE Older age and poor performance status at presentation are unfavorable prognostic factors for patients with glioblastoma multiforme. Some studies suggest a shorter, palliative course of radiotherapy may confer similar benefits as compared to a radical course in such patients. We report a prospective, single arm trial, describing the use of a short-course of radiation in patients with glioblastoma and poor prognostic features. METHODS AND MATERIALS Twenty-nine patients with pathologically confirmed glioblastoma and age > or = 65 years or with initial KPS < or = 50 were treated with a short-course of whole brain radiotherapy (30 Gy/10 fractions/2 weeks). Computer tomography tumor volume, dexamethasone requirements, Spitzer quality of life index, and Karnofsky performance status were measured pre and 1 month postradiation. Overall survival for the study patients was compared with that of radically treated and supportive care only historical controls. RESULTS Indices of tumor response were stable or improved in 60% of patients evaluable 1 month postradiotherapy. Median survival for all study patients was 6 months. Median survivals in similar groups of radically treated and supportive care only patients were 10 and 1 month(s), respectively. A survival advantage for the radical vs. short-course treatment was observed for the subset of patients with a pretreatment KPS > 50. CONCLUSION Elderly patients with a low pretreatment KPS (< or = 50) may be treated adequately with a short, palliative course of radiotherapy. Elderly patients with a higher pretreatment KPS (> 50), however, may benefit from a higher dose radiotherapy regimen.

Reirradiation of primary CNS tumors

PURPOSE Primary central nervous system (CNS) tumors are seldom reirradiated due to toxicity concerns and sparse clinical data regarding efficacy. METHODS AND MATERIALS We retrospectively reviewed 34 patients with primary brain tumors retreated with fractionated external beam irradiation at the University of California, San Francisco from 1977-1993. Tumors included 15 medulloblastomas, 10 high-grade gliomas, 7 low-grade gliomas, and 2 meningiomas. RESULTS Initial course of radiation was radical in intent for all patients. Median age at initial diagnosis was 19.8 years (range: 3.6-67). Median interval between radiation courses was 16.3 months (range: 3.8-166). Median Karnofsky Performance Status (KPS) prior to reirradiation was 80 (range: 40-100). Reirradiation volumes overlapped previous treatment in 30 patients and were nonoverlapping in 4 patients. Fractionation schemes used were hyperfractionated in 17, conventionally fractionated in 9, and hypofractionated in 8. Cumulative maximum overlap dose within the CNS ranged from 43.2-111 Gy (median: 79.7 Gy). Retreatment was completed as planned in 27 out of 34 patients and modified or aborted in 7 (four tumor progression on retreatment, three patient request). As measured from the time of retreatment median progression free and overall survival was 3.3 and 8.3 months. Clinical and radiographic indices were stabilized or improved in about half of patients evaluable at a median of 3 months postretreatment. Complications (early or late) potentially attributable to retreatment were noted in 10 of 34 (29%) of patients. Overt necrosis was noted in 3 of 34 (9%) of patients and the actuarial risk of necrosis was 22% at 1 year following retreatment. CONCLUSIONS Reirradiation of primary central nervous system tumors was associated with only modest palliative and survival benefits in this retrospective review. Difficulties separating toxicity due to retreatment vs. tumor progression and limited patient survival following retreatment preclude definite conclusions regarding the safety of this practice.

Ki-67: A prognostic factor for low-grade glioma?

PURPOSE Immunohistochemical techniques were used to detect the expression of Ki-67, a nuclear proliferation marker, in 180 low-grade glioma tumor specimens to determine whether Ki-67 is a prognostic predictor of survival or tumor recurrence. MATERIALS AND METHODS A clinical database of 180 low-grade glioma patients (35 children aged </=18 years and 145 adults) was compiled. Eighty patients had received postoperative radiotherapy (RT) and 100 patients had had RT deferred until the time of tumor progression/recurrence. Ki-67 indexes were evaluated retrospectively on tumor specimens from these patients using a semiautomated computer analysis technique. Ten observations were averaged per patient. The maximal Ki-67 value was recorded. RESULTS The correlation between the Ki-67 index and survival was much higher for the averaged Ki-67 value than for the maximal value. Of the tumor specimens, 29% had a negative Ki-67 index (i.e., zero Ki-67 positive cells) and 7.7% had an average Ki-67 index of >/=5%. An average Ki-67 value of >/=5% was prognostically significant for reduced cause-specific survival (CSS, p = 0.05) and a Ki-67 level >/=10% was strongly significant of a poor survival outcome (p = 0.009). Ki-67 was not prognostically significant for progression-free survival. Other prognostically significant factors for CSS included age (p = 0.05), Karnofsky performance status (p = 0.0001), radiation dose (p = 0.02), extent of surgical resection (biopsy vs. others, p = 0.004), and timing of radiation (p = 0.0005). Ki-67 did not remain an independent statistically significant factor for CSS on multivariate analysis. Age and Ki-67 positivity (both maximal and average values) directly correlated (i.e., advancing age was associated with a higher Ki-67 index). When the patient group was further subdivided by age and timing of RT (postoperative vs. deferred), the prognostic significance of Ki-67 for CSS was lost. Within the deferred RT subgroup, a maximal Ki-67 >2% was associated with a worsened CSS. Within the pediatric population, Ki-67-negative patients had a 5-year CSS and progression-free survival of 100%. The 5-year CSS and progression-free survival declined significantly to 84% and 67% for patients with tumors demonstrating any degree of Ki-67 positivity (p = 0.005 and p = 0.006, respectively). CONCLUSION Ki-67 is a useful predictor of CSS in low-grade gliomas; however, it is not independent of other prognostic factors, particularly age. Although Ki-67 was not helpful in predicting which adult patients were likely to benefit from postoperative RT, the results of the present study indicate a possible utility in the selection of pediatric patients for RT and in the selection of poorer prognosis patients for clinical trials.

Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer

Purpose Men with localized prostate cancer often are treated with external radiotherapy (RT) over 8 to 9 weeks. Hypofractionated RT is given over a shorter time with larger doses per treatment than standard RT. We hypothesized that hypofractionation versus conventional fractionation is similar in efficacy without increased toxicity. Patients and Methods We conducted a multicenter randomized noninferiority trial in intermediate-risk prostate cancer (T1 to 2a, Gleason score ≤ 6, and prostate-specific antigen [PSA] 10.1 to 20 ng/mL; T2b to 2c, Gleason ≤ 6, and PSA ≤ 20 ng/mL; or T1 to 2, Gleason = 7, and PSA ≤ 20 ng/mL). Patients were allocated to conventional RT of 78 Gy in 39 fractions over 8 weeks or to hypofractionated RT of 60 Gy in 20 fractions over 4 weeks. Androgen deprivation was not permitted with therapy. The primary outcome was biochemical-clinical failure (BCF) defined by any of the following: PSA failure (nadir + 2), hormonal intervention, clinical local or distant failure, or death as a result of prostate cancer. The noninferiority margin was 7.5% (hazard ratio, < 1.32). Results Median follow-up was 6.0 years. One hundred nine of 608 patients in the hypofractionated arm versus 117 of 598 in the standard arm experienced BCF. Most of the events were PSA failures. The 5-year BCF disease-free survival was 85% in both arms (hazard ratio [short v standard], 0.96; 90% CI, 0.77 to 1.2). Ten deaths as a result of prostate cancer occurred in the short arm and 12 in the standard arm. No significant differences were detected between arms for grade ≥ 3 late genitourinary and GI toxicity. Conclusion The hypofractionated RT regimen used in this trial was not inferior to conventional RT and was not associated with increased late toxicity. Hypofractionated RT is more convenient for patients and should be considered for intermediate-risk prostate cancer.

ADULT SUPRATENTORIAL LOW-GRADE GLIOMA: LONG-TERM EXPERIENCE AT A SINGLE INSTITUTION

PURPOSE To report the long-term follow-up of a cohort of adult patients with supratentorial low-grade glioma treated at a single institution. METHODS AND MATERIALS A cohort of 145 adult patients treated at the London Regional Cancer Program between 1979 and 1995 was reviewed. RESULTS With a median follow-up of 105 months, the median progression-free survival was 61 months (95% confidence interval, 53-77), and the median overall survival was 118 months (95% confidence interval, 93-129). The 10- and 20-year progression-free and overall survival rate was 18% and 0% and 48% and 22%, respectively. Cox regression analysis confirmed the importance of age, histologic type, presence of seizures, Karnofsky performance status, and initial extent of surgery as prognostic variables for overall and cause-specific survival. Function among long-term survivors without tumor progression was good to excellent for most patients. CONCLUSION Low-grade glioma is a chronic disease, with most patients dying of their disease. However, long-term survival with good function is possible. Survival is determined primarily by the disease factors with selection and timing of adjuvant treatments having less influence on outcome.