A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results.

PURPOSE: This phase III trial compared adjuvant whole-brain radiotherapy (WBRT) with observation after either surgery or radiosurgery of a limited number of brain metastases in patients with stable solid tumors. Here, we report the health-related quality-of-life (HRQOL) results. PATIENTS AND METHODS: HRQOL was a secondary end point in the trial. HRQOL was assessed at baseline, at 8 weeks, and then every 3 months for 3 years with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and Brain Cancer Module. The following six primary HRQOL scales were considered: global health status; physical, cognitive, role, and emotional functioning; and fatigue. Statistical significance required P ≤ .05, and clinical relevance required a ≥ 10-point difference. RESULTS: Compliance was 88.3% at baseline and dropped to 45.0% at 1 year; thus, only the first year was analyzed. Overall, patients in the observation only arm reported better HRQOL scores than did patients who received WBRT. The differences were statistically significant and clinically relevant mostly during the early follow-up period (for global health status at 9 months, physical functioning at 8 weeks, cognitive functioning at 12 months, and fatigue at 8 weeks). Exploratory analysis of all other HRQOL scales suggested worse scores for the WBRT group, but none was clinically relevant. CONCLUSION: This study shows that adjuvant WBRT after surgery or radiosurgery of a limited number of brain metastases from solid tumors may negatively impact some aspects of HRQOL, even if these effects are transitory. Consequently, observation with close monitoring with magnetic resonance imaging (as done in the EORTC trial) is not detrimental for HRQOL.

Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study.

PURPOSE: This European Organisation for Research and Treatment of Cancer phase III trial assesses whether adjuvant whole-brain radiotherapy (WBRT) increases the duration of functional independence after surgery or radiosurgery of brain metastases. PATIENTS AND METHODS: Patients with one to three brain metastases of solid tumors (small-cell lung cancer excluded) with stable systemic disease or asymptomatic primary tumors and WHO performance status (PS) of 0 to 2 were treated with complete surgery or radiosurgery and randomly assigned to adjuvant WBRT (30 Gy in 10 fractions) or observation (OBS). The primary end point was time to WHO PS deterioration to more than 2. RESULTS: Of 359 patients, 199 underwent radiosurgery, and 160 underwent surgery. In the radiosurgery group, 100 patients were allocated to OBS, and 99 were allocated to WBRT. After surgery, 79 patients were allocated to OBS, and 81 were allocated to adjuvant WBRT. The median time to WHO PS more than 2 was 10.0 months (95% CI, 8.1 to 11.7 months) after OBS and 9.5 months (95% CI, 7.8 to 11.9 months) after WBRT (P = .71). Overall survival was similar in the WBRT and OBS arms (median, 10.9 v 10.7 months, respectively; P = .89). WBRT reduced the 2-year relapse rate both at initial sites (surgery: 59% to 27%, P < .001; radiosurgery: 31% to 19%, P = .040) and at new sites (surgery: 42% to 23%, P = .008; radiosurgery: 48% to 33%, P = .023). Salvage therapies were used more frequently after OBS than after WBRT. Intracranial progression caused death in 78 (44%) of 179 patients in the OBS arm and in 50 (28%) of 180 patients in the WBRT arm. CONCLUSION: After radiosurgery or surgery of a limited number of brain metastases, adjuvant WBRT reduces intracranial relapses and neurologic deaths but fails to improve the duration of functional independence and overall survival.

Pineocytoma and pineal parenchymal tumors of intermediate differentiation presenting cytologic pleomorphism: a multicenter study.

Cytologic pleomorphism has been described in a limited number of benign pineal tumors, namely pineocytoma (PC) and pineal parenchymal tumors (PPTs) of intermediate differentiation (PPTID). We examined the clinicopathologic features in a retrospective series of 14 cases (seven females and seven males aged from 10 to 65 years) of pleomorphic PPT. Seven cases were PC, with no mitoses and with areas of tumoral cells forming large pineocytomatous rosettes and other areas with giant cells containing hyperchromatic nuclei. The other seven were PPTID, presenting few mitoses (< or =2), a Ki67 proliferation index between 3% and 7%, and predominantly composed of small neoplastic cells and scattered giant cells, sometimes multinucleated. In the 14 tumors, the proportion of pleomorphic areas was variable. Most tumoral cells showed extensive neuronal differentiation with strong expression of neuron-specific enolase, synaptophysin and neurofilaments. Some of the neoplastic cells expressed S100 protein. The follow-up period ranged from 1.2 to 13 years and only one PC and one PPTID progressed after stereotactic biopsy or incomplete resection. The lack of invasiveness and the low proliferation index of these tumors suggest a benign clinical course despite the marked pleomorphism, the latter of which can lead to upgrading.

Prognosis and histopathologic features in papillary tumors of the pineal region: a retrospective multicenter study of 31 cases.

Papillary tumor of the pineal region (PTPR) is a recently described tumor entity thought to arise from the specialized ependyma of the subcommissural organ. Whereas histologic features of PTPR are well defined, data on the prognostic value of PTPR remain scarce. We therefore investigated clinicopathologic features, including data on progression-free survival and overall survival, in a retrospective series of 31 PTPR. The age of the 14 males and 17 females ranged from 5 to 66 years (median age, 29 years). Histologically, all tumors were characterized by an epithelial-like growth pattern in which the vessels were covered by layers of columnar or cuboidal tumor cells forming perivascular pseudorosettes. Most of the tumor cells showed strong expression of neuron-specific enolase, cytokeratins (particularly CK18), S-100 protein, and vimentin. Most PTPRs examined also expressed microtubule-associated protein-2. Expression of synaptophysin, epithelial membrane antigen, transthyretin, neural cell adhesion molecule, and nestin was encountered in some tumors. Gross total resection could be achieved in 21 of 31 cases; 15 patients received radiotherapy on resection of the primary tumor. Nevertheless, the majority of patients experienced recurrences; 5-year estimates for overall survival and progression-free survival were 73% and 27%, respectively. To conclude, the clinical course of PTPR is characterized by frequent local recurrence, and the value of radiotherapy on disease progression will need to be investigated in future prospective trials.

Atlas-based automatic segmentation of MR images: validation study on the brainstem in radiotherapy context.

PURPOSE: Brain tumor radiotherapy requires the volume measurements and the localization of several individual brain structures. Any tool that can assist the physician to perform the delineation would then be of great help. Among segmentation methods, those that are atlas-based are appealing because they are able to segment several structures simultaneously, while preserving the anatomy topology. This study aims to evaluate such a method in a clinical context. METHODS AND MATERIALS: The brain atlas is made of two three-dimensional (3D) volumes: the first is an artificial 3D magnetic resonance imaging (MRI); the second consists of the segmented structures in this artificial MRI. The elastic registration of the artificial 3D MRI against a patient 3D MRI dataset yields an elastic transformation that can be applied to the labeled image. The elastic transformation is obtained by minimizing the sum of the square differences of the image intensities and derived from the optical flow principle. This automatic delineation (AD) enables the mapping of the segmented structures onto the patient MRI. Parameters of the AD have been optimized on a set of 20 patients. Results are obtained on a series of 6 patients' MRI. A comprehensive validation of the AD has been conducted on performance of atlas-based segmentation in a clinical context with volume, position, sensitivity, and specificity that are compared by a panel of seven experimented physicians for the brain tumor treatments. RESULTS: Expert interobserver volume variability ranged from 16.70 cm(3) to 41.26 cm(3). For patients, the ratio of minimal to maximal volume ranged from 48% to 70%. Median volume varied from 19.47 cm(3) to 27.66 cm(3) and volume of the brainstem calculated by AD varied from 17.75 cm(3) to 24.54 cm(3). Medians of experts ranged, respectively, for sensitivity and specificity, from 0.75 to 0.98 and from 0.85 to 0.99. Median of AD were, respectively, 0.77 and 0.97. Mean of experts ranged, respectively, from 0.78 to 0.97 and from 0.86 to 0.99. Mean of AD were, respectively, 0.76 and 0.97. CONCLUSIONS: Results demonstrate that the method is repeatable, provides a good trade-off between accuracy and robustness, and leads to reproducible segmentation and labeling. These results can be improved by enriching the atlas with the rough information of tumor or by using different laws of deformation for the different structures. Qualitative results also suggest that this method can be used for automatic segmentation of other organs such as neck, thorax, abdomen, pelvis, and limbs.

Phase II study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme.

Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavours, with low response rates and survival rarely exceeding 6 months. There are no standard chemotherapeutic regimens and new therapeutic approaches have to be found. We report an open-label, uncontrolled, multicentre phase II trial of lonidamine (LND) and diazepam in 16 patients with GBM at first relapse and a Karnofsky performance status > or = 70. The treatment regimen consisted of LND 450 mg/day and diazepam 15 mg/day orally of every 28-day cycle until progression or unacceptable toxicity. Patients received a median of three cycles (range, 1-12). No complete or partial response was observed. Therefore, according to the design of the study, no additional patients were enrolled and the trial was closed. Nevertheless, seven stabilizations (50%) were observed. Median time to progression was 8 weeks (range, 5-19 weeks). Median overall survival from recurrence was 15 weeks (range, 14-61 weeks). No grade 3-4 toxicity, except somnolence, was observed and there were no therapy-related deaths. Dose reduction for diazepam due to somnolence (grade III) was performed in 9 patients. The combination of LND and diazepam is well tolerated. LND and diazepam, acting on two distinct mitochondrial sites involved in cellular energy metabolism, may exert a cytostatic effect on tumour growth as shown by the high percentage of stable patients. The LND-diazepam at the used dosing schedule did not show a complete or partial response. LND plus diazepam may be interesting in the adjuvant setting or associated to chemotherapy to act on different targets and increase the therapeutic index.

Papillary tumor of the pineal region.

Primary papillary tumors of the central nervous system are rare. We have encountered a series of six papillary tumors of the pineal region with distinctive features that appear to represent a clinicopathologic entity. The tumors occurred in four women and two men, ranging in age from 19 to 53 years. Imaging studies showed a large well-circumscribed mass in the pineal region. The tumors were characterized by an epithelial-like growth pattern, in which the vessels were covered by a layer of tumoral cells. In papillary areas, the neoplastic cells were large, columnar or cuboidal, with a clear cytoplasm. Nuclei, round or infolded, were found generally at the basal pole of tumoral cells. Immunohistochemically, the tumor cells showed strong staining for cytokeratin, S-100 protein, neuron-specific enolase, and vimentin but only weak or no staining for epithelial membrane antigen and glial fibrillary acid protein. Ultrastructural examination of two cases revealed abundant rough endoplasmic reticulum with distended cisternae filled with secretory product, microvilli, and perinuclear intermediate filaments. The morphofunctional features of these papillary tumors of the pineal region, remarkably uniform within this series, are similar to those described for ependymal cells of the subcommissural organ, and the papillary tumors of the pineal region may be derived from these specialized ependymocytes.

Malignant pineal parenchymal tumors in adult patients: patterns of care and prognostic factors.

OBJECTIVE: The aim of our study was to analyze patterns of care and to identify prognostic factors in patients at least 18 years of age who received radiotherapy for malignant pineal parenchymal tumors. METHODS: In a multicenter, retrospective study, we analyzed data for 37 previously published cases and 64 patients treated at the participating institutions. RESULTS: A total of 56 patients received postoperative radiotherapy, and 45 patients received primary radiotherapy. Chemotherapy was administered to 34 patients. The median follow-up period was 38 months, and median overall survival was 100 months. The variables that significantly influenced overall survival were the extent of disease (localized versus disseminated; P = 0.0002), differentiation (pineal parenchymal tumor of intermediate differentiation versus pineoblastoma; P = 0.001), and residual disease (> or = 50% versus < 50% reduction in size; P < 0.0001). In a multivariate analysis, the parameters turned out to be independent risk factors. The median survival in patients with local or spinal failure was 15 months. Local control was better in older patients (> or = 32 yr versus < 32 yr; P = 0.02). Spinal control was more successful in patients with pineal parenchymal tumors of intermediate differentiation than it was in patients with pineoblastomas (P = 0.03). Nine of 45 treatment failures occurred later than 5 years after treatment. CONCLUSION: Stage, histological characteristics, and response are independent risk factors in adults with malignant pineal parenchymal tumors. Late relapses are common.