Proteomic profiles differ between bone invasive and noninvasive benign meningiomas of fibrous and meningothelial subtype

Meningiomas of WHO grade I can usually be cured by surgical resection. However, some tumors may, despite their benign appearance, display invasive growth behavior. These tumors constitute a difficult clinical problem to handle. By histology alone, bone invasive meningiomas may be indistinguishable from their noninvasive counterparts. In this study we have examined the protein spectra in a series of meningiomas in search of protein expression patterns that may distinguish between bone invasive and noninvasive meningiomas. Tumor tissue from 13 patients with fibrous (6 invasive and 7 noninvasive) and 29 with meningothelial (10 invasive and 19 noninvasive) grade I meningiomas were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI). Multivariate statistical methods were applied for data analyses. Comparing the protein spectra from invasive and noninvasive fibrous meningioma we found 22 peaks whose intensities were significantly different between the two groups (P < 0.001). Based on the expression pattern of these peaks we were able to perfectly separate the two entities (area under ROC curve = 1.0). In meningothelial meningioma the same comparison yielded six significantly differentially expressed peaks (P < 0.001), which to a large degree separated the invasive from noninvasive tissue (area under ROC curve = 0.873). By analyzing the protein spectra in benign meningiomas we could differentiate between invasive and noninvasive growth behavior in both fibrous and meningothelial meningiomas of grade I. A possibility for early identification of invasive grade I meningiomas may have a strong influence on the follow-up policy and the issue of early or late radiotherapy.     

Meningioma of the skull base: Long-term outcome after image-guided stereotactic radiotherapy

PurposeThe purpose of this study was to analyse the feasibility, safety, and long-term efficacy of linear accelerator-based fractionated stereotactic radiotherapy for meningiomas of the skull base. We evaluated the long-term clinical outcome of patients and identified prognostic factors after fractionated stereotactic radiotherapy.Patients and methodsBetween 10/1995 and 03/2009, 136 patients with a median age of 57 years with skull base meningioma received fractionated stereotactic radiotherapy. A total of 34 patients had a grade I meningioma, in 102 cases no histology was obtained (grade 0). Fractionated stereotactic radiotherapy was delivered as primary treatment for 57 patients and postoperatively for 79. The patients received a mean total dose of 56.95 (min/max 32.4/63) Gy.ResultsMedian follow-up was 44.9 months. Overall progression-free survival was 96.9% after 3 years, 93.8% after 5 years, and 91.5% after 10 years. Patients with unknown histology showed progression-free survival rates of 100%, 98.7%, and 93.5% at 3, 5, and 10 years and patients with biopsy-proven grade I meningioma showed rates of 100% after 3 years, 91.7% after 5 years and 85.9% after 10 years. Patients with adjuvant radiotherapy showed significantly worse progression-free survival rates than patients who had been treated with primary radiotherapy (P = 0.043), progression-free survival rates were independent of tumour size. The most common acute grade I symptoms were headache, fatigue, and local alopecia. The most common chronic grade I symptoms were fatigue and headache.ConclusionsThis large study showed that fractionated stereotactic radiotherapy is an effective and safe treatment modality with high progression-free survival rates for intracranial meningioma. We identified “prior surgery” as significant poor prognostic factor.     

Fractionated stereotactic radiation therapy in the management of primary optic nerve sheath meningiomas

We analysed our long-term results after fractionated stereotactic radiotherapy (FSRT) in patients with primary optic nerve sheath (pONSM) meningioma, as a rare subtype of meningiomas. Between 01/1995 and 12/2007, 32 patients with pONSM were treated with FSRT. Fifteen patients received radiotherapy as primary treatment, four after biopsy, and six patients after surgical resection. Seven patients were irradiated for recurrent disease. Seventeen lesions were histologically proven and determined as WHO grade I pONSM. Median target volume was 15.7 cc, median total dose 54.9 Gy. Twenty-nine patients showed clinical symptoms before radiotherapy like reduced vision, unilateral loss of vision, or an exophthalmia. Median follow-up was 4.5 years. Overall local tumor control was 100%. Twenty-six patients had stable disease based on CT/MRI, while 6/32 had a partial remission of tumor volume. 97% of our patients showed stable vision or an improvement of visual acuity. Eleven patients (38%) showed an improvement of pre-existing clinical symptoms like double vision, exophthalmia and visual acuity. Only one patient showed an impairment of vision with progressive concentric decreasing of the visual field on the side of the irradiated ONSM. These data demonstrate that FSRT is an effective and safe treatment modality for local control in patients with pONSM with minimal risk of significant late toxicity.     

Hydroxyurea for recurrent surgery and radiation refractory high-grade meningioma

Hydroxyurea (HU), an orally administered chemotherapy, has become the de facto standard chemotherapeutic agent in patients with surgically and radiation refractory meningiomas based on a limited literature. A retrospective case series of 35 patients with recurrent WHO Grade 2 (n = 22) or 3 (n = 13) meningioma treated with HU following progression after surgery and radiotherapy was collated with primary study objectives of overall response rate, median and progression free survival (PFS) at 6-months. Thirty-five patients (25 women; 10 men: median age 63 years, range 34–86) with recurrent high-grade meningioma were treated with HU (1,000 mg/m² orally divided twice per day; one cycle operationally defined as 4 weeks of daily HU). Patients had progressed radiographically after prior therapy with surgery (35/35) and radiotherapy (35/35: external beam radiotherapy 35/35; stereotactic radiotherapy 35/35). No patient received prior chemotherapy or targeted therapy before instituting HU. Patients received 0.5–7 cycles (median 2.0) of HU with modest toxicity (28.5% all grades and 8.5% grade 3+ anemia or fatigue). There were no radiographic responses, 43% of patients had stable disease and 57% manifested progressive disease at first evaluation. The overall PFS was 3.0% at 6 months (median PFS 2.0 months; 95% CI 1.6–2.4). The majority of patients (80%) following progression on HU were subsequently treated on an investigational trial. In this retrospective series, HU though well tolerated and convenient appeared to have very limited activity, raise questions of what constitutes effective salvage therapy and indicates an unmet need for alternative treatments for recurrent high-grade meningiomas.     

Tumor grade-related <Emphasis Type="Italic">NDRG2</Emphasis> gene expression in primary and recurrent intracranial meningiomas

Approximately 30% of all primary CNS tumors are meningiomas. Depending on histological type, meningiomas can recur as follows: benign—with five-year recurrence of 5%, atypical—recurrence approximately 40%, and anaplastic with recurrence of 50–80%. In an attempt to understand the molecular mechanism of meningioma recurrence we investigated the N-Myc downstream-regulated gene 2 (NDRG2), which has recently been described as important in suppressing cellular carcinogenesis in different types of cancer. The objective of the study was to investigate NDRG2 gene expression at the mRNA level in primary and recurrent meningiomas as a potential marker of tumor aggressiveness, malignancy, and recurrence. Primary and recurrent meningiomas of WHO grades I, II, and III from 35 patients operated on between 2005 and 2008 year at the Department of Neurosurgery of Kaunas Medical University Hospital (Lithuania) were studied. Using the qRT-PCR method we measured NDRG2 gene expression at the mRNA level in primary (n = 24) and recurrent (n = 11) meningiomas. Statistically significant differences in NDRG2 gene expression level were observed between primary and recurrent meningioma groups (P < 0.05) and between benign (WHO grade I) and atypical (WHO grade II) meningiomas (P < 0.05). No statistically significant differences were observed (P > 0.05) among histological subtypes of benign (WHO grade I) meningiomas: fibrous, meningothelial, and transitional. In accordance with our results, reduction of NDRG2 gene expression at the mRNA level could help to explain malignant progression and predisposition to recurrence in meningiomas.     

Intracranial relapse rates and patterns,and survival trends following post-resection cavity radiosurgery for patients with single intracranial metastases

The objective of this study is to evaluate the patterns of relapse and survival trends in patients with single brain metastases treated with post-operative adjuvant Gamma knife stereotactic radiosurgery (GKS) without whole brain radiotherapy (WBRT). Retrospective analysis of all consecutive patients who underwent GKS to the tumor cavity following resection of solitary brain metastasis was performed at a single institution. Between March 2001 and June 2010, 56 patients underwent GKS to the resection cavity following resection of intracranial metastases; no patient received pre- or post-operative WBRT as an adjuvant (salvage WBRT was permissible). The mean marginal dose was 17.1 Gy (range 14–20 Gy). The mean follow-up period was 24 months (range 3–99 months). Five patients (8.9%) had local recurrence in the immediate vicinity of the resection cavity, qualifying as “local failures”, and 21 (37.5%) recurred at distant intracranial sites. Median intracranial recurrence free survival was 13 months. Median overall survival was 20.5 months. Salvage interventions were required in 26 patients, and included repeat radiosurgery in 17 patients, further surgery in two patients, and salvage WBRT in eight (14.3%; two of whom had also been locally salvaged with repeat radiosurgery) patients. As expected, avoidance of WBRT results in a high rate of intracranial failure (26/56 patients, 46%), even in well-selected patients with only single brain metastases. As anticipated, the majority of failures (21, 37.5%) are “distant intracranial”, and in this well-selected cohort the local failure rate is low (5/56 patients, <9%). All patients failing intracranially (46%) are potential candidates for salvage therapies, but WBRT as salvage was utilized in only 14.3% of patients. The median intracranial relapse-free was 13 months and overall survival was 20.5 months.     

WHO grade II and III meningiomas: a study of prognostic factors

Meningiomas represent one of the largest subgroups of intracranial tumors. They are generally benign, but may show a histological progression to malignancy. Grades II and III meningiomas have been less well studied and are not well controlled because of their aggressive behaviour and recurrences. There is no consensus on therapeutic strategies and no prognostic factors are known. In order to determine these parameters, a multi-institutional retrospective analysis was performed in France with the support of the Neuro-Oncology Club of the French Neurosurgical Society. This study was performed on 199 adults treated for WHO grade II (166 patients) or grade III (33 patients) meningiomas between 1990 and 2004 in the Neurosurgery Departments of five French University Hospitals. Data on epidemiology, clinical behaviour and therapy were collected. Overall survival and progression-free survival were analysed as a function of each possible prognostic factor. For patients with grade II meningiomas, the 5- and 10-year OS rates were 78.4 and 53.3%, respectively, while, for patients with grade III meningiomas, the corresponding values were 44.0 and 14.2%. For patients with grade II meningiomas, the 5- and 10-year PFS rates were 48.4 and 22.6%, respectively, the corresponding values for patients with grade III meningiomas being 8.4 and 0%. For the grade II meningiomas, univariate analysis showed that age < 60 years (P < 0.0001) and Simpson 1 resection (P = 0.055) were associated with a longer OS. For the grade III meningiomas, univariate analysis showed that age < 60 years (P < 0.0001) and RT (P = 0.036) were associated with a longer OS. Histological grade II was found to be associated with a longer PFS (P = 0.0032) and RT reduced the PFS in grade II meningiomas (P = 0.0006) There were no other prognostic factors in terms of PFS for grades II and III meningiomas in univariate analysis. Multivariate analysis confirmed that age (< 60 years), Simpson 1 and histological grade II were independent prognostic factors for survival. This retrospective study might improve the management of grades II and III meningiomas. Prospective trials should delineate strong therapeutic guidelines for high-grade meningiomas.     

Hydroxyurea for recurrent surgery and radiation refractory meningioma: a retrospective case series

Hydroxyurea (HU), an orally administered chemotherapy, has become the de facto standard therapeutic agent in patients with surgically and radiation refractory meningiomas based on a limited literature. A retrospective case series of 60 patients with recurrent WHO grade 1 meningioma treated with HU following progression after surgery and radiotherapy was conducted with primary study objective progression free survival (PFS) at 6- and 12-months. Sixty patients (45 women; 15 men: median age 61.5 years, range 26–88) with recurrent meningioma were treated with HU (1000 mg/m²/day orally divided twice per day; one cycle operationally defined as 4-weeks of daily HU). All patients had progressed radiographically after prior therapy with surgery (60/60) and radiotherapy (external beam radiotherapy 60/60; stereotactic radiotherapy 53/60). No patient received prior chemotherapy or targeted therapy before instituting HU. Patients received 1-12 cycles (median 2.0) of HU with modest toxicity (10% grade 3 + anemia or fatigue). There were no radiographic responses, 35% of patients had stable disease and 65% manifested progressive disease. Duration of stable disease ranged from 3 to 12 months (median 4.0 months). The overall PFS was 10% (median PFS 2.0 months). The majority of patients (80%) following progression on HU were subsequently treated on an investigational trial. In this retrospective case series, HU though generally well tolerated and convenient, appeared to have very limited activity which raises questions of what constitutes effective salvage therapy and indicates an unmet need for alternative treatments for recurrent meningiomas.     

Fractionated stereotactic radiation therapy in the management of primary oligodendroglioma and oligoastrocytoma

PURPOSE: To retrospectively analyze the outcomes and benefits from radiation therapy (RT) as a component of multimodal treatment for oligodendroglioma and oligoastrocytoma, assessing local control and survival rates and evaluating prognostic factors. METHODS AND MATERIALS: We retrospectively reviewed 56 adult patients with supratentorial oligodendroglioma or oligoastrocytoma treated at our institution from January 1990 to December 2003 with fractionated stereotactic RT (FSRT). RESULTS: Fractionated stereotactic RT was well tolerated in all patients, without side effects. Median survival and progression-free survival calculated from the initiation of radiotherapy were 48 months (range, 2-133 months) and 38 months (range, 2-132 months), respectively. Progression-free survival rates after radiation were 89% at 1 year and 52% at 5 years. Of 26 recurrences, 92% developed in field. With regard to histology, overall survival rates in the World Health Organization (WHO) Grade II group were 89% and 74% at 5 and 10 years, respectively. In patients with WHO Grade III tumors, overall survival rates at 5 and 10 years were 69% and 46%, respectively. No prognosticators could be identified for median survival and progression-free survival after radiotherapy. Median overall survival calculated from primary diagnosis was 77.5 months (range, 3-214 months). The Cox regression multivariate analysis for age and neurologic symptoms showed a significance of p = 0.003 for age and p = 0.037 for the presence of neurologic symptoms on overall survival since primary diagnosis. CONCLUSIONS: Commonly, conventional conformal RT is applied in the treatment of brain tumors. In FSRT, the tumor volume can be irradiated with high doses, sparing volume of normal brain tissue. Our data are in accordance with survival times found in the literature. Ninety-two percent of all recurrences occurred within the defined target volume, confirming that reduction of the RT portals by the use of FSRT does not lead to an increased rate of recurrences at the field border or out of field. Fractionated stereotactic RT can therefore be implemented as an effective and safe modality in the therapy of primary oligodendroglioma and oligoastrocytoma.     

Stereotactic radiosurgery eligibility and selection bias in the treatment of glioblastoma multiforme

Several single institution studies have shown a survival advantage when a stereotactic radiosurgery (SRS) boost followed fractionated external beam radiation (FracRT) in the treatment of glioblastoma (GBM). RTOG 93-05 employed SRS before FracRT and demonstrated no survival benefit. We examined the effect of SRS eligibility before and after FracRT on patient outcome in a group of patients treated with conventional therapy without SRS. From 1998 to 2008, 106 patients with GBM treated definitively at the University of Utah were divided into groups based on eligibility for SRS: ineligible (“Never”), eligible before FracRT (“All Pre”), eligible before FracRT only (“Pre Only”), or eligible before and after FracRT (“Always”). Overall (OS) and progression-free survival (PFS) based on SRS eligibility was assessed. Eleven patients were alive at the time of analysis with a median follow-up of 42.3 months. Median OS for groups “All Pre” (n = 29), “Always” (n = 17), “Pre Only” (n = 12), and “Never” (n = 77) were 13.6, 13.6, 12.4, and 9.2 months, respectively. Of the 29 patients in group “All Pre,” 12 (41.4%) were ineligible for SRS following FracRT. PFS did not significantly differ between groups. SRS for GBM can only be of benefit to selected patients with minimal focal postoperative disease. Following FracRT, over a third of initially SRS-eligible patients demonstrated more extensive disease in our experience. It is possible inclusion of such patients in a series of SRS for GBM could mask a benefit in remaining patients. No significant difference in OS or PFS based on SRS-eligibility status was found.     

Differential effect of surgery and radiotherapy on neurocognitive functioning and health-related quality of life in WHO grade I meningioma patients

Background Potential treatment-related neurotoxicity and the indolent course of the disease mainly feed the controversy concerning the optimal timing of surgery and radiotherapy in meningioma patients. Object To quantify the additional negative effects of conventional radiotherapy compared to surgery alone on neurocognitive functioning and health-related quality of life (HRQOL) in patients with WHO grade I meningiomas. Methods Neurocognitive functioning and HRQOL (SF36, EORTC-BCM20) were assessed in consecutive patients (1999–2005) with WHO grade I meningiomas at least 1 year after surgical treatment in two centers for brain tumor patients. Subsequently, we selected all patients who underwent surgery and conformal external beam fractioned radiotherapy (n = 18) and matched these patients for age, sex, and educational level with the same number of patients who had had surgery only (n = 18), as well as with the same number of healthy controls. Results No significant differences in neurocognitive functioning were found between the two meningioma patient groups; however, even meningioma patients who were treated with surgery only had a significantly lower neurocognitive functioning than healthy controls. Meningioma patients who were treated with surgery and radiotherapy had significantly lower HRQOL scores than meningioma patients who were treated with surgery only, who had HRQOL ratings comparable with healthy controls; these differences, however, disappeared after correction for the duration of disease. Conclusions In contrast with conventional thinking, long-term neurocognitive functioning was significantly impaired in our meningioma patients. Additional radiotherapy following surgery, however, does not have additional deleterious effects on neurocognitive outcome in these patients.     

Expression of phosphoprotein enriched in astrocytes 15 kDa (PEA-15) in astrocytic tumors: a novel approach of correlating malignancy grade and prognosis

Phosphoprotein enriched in astrocytes 15 kDa (PEA-15) is a multifunctional protein that was first identified in brain astrocytes and that has subsequently been shown to be expressed in different tissues. Despite its many important roles, the clinical significance of PEA-15 expression levels in astrocytic tumors has yet to be properly defined. We studied the PEA-15 expression pattern of 65 patients [diagnosed according to World Health Organization (WHO) criteria] with diffuse astrocytoma (WHO grade II), anaplastic astrocytoma (grade III), and glioblastoma (grade IV). PEA-15 expression levels were immunohistochemically measured and categorized as no, low, or high expression. All tumors expressed PEA-15 in our study. Twenty-three (35.4%) and 42 (64.6%) tumors expressed low and high PEA-15 levels, respectively. In grade II astrocytoma (diffuse astrocytoma) and grade III astrocytoma (anaplastic astrocytoma), 100% and 88.9% of patients expressed high PEA-15 levels, respectively, while a smaller number (50%) of patients with grade IV astrocytoma (glioblastoma) expressed high PEA-15 levels. PEA-15 expression level was inversely associated with WHO grade (P = 0.0006). Next, we evaluated prognosis and PEA-15 expression levels in 43 patients with high-grade astrocytomas based on the following parameters: age, gender, WHO grade, surgical resection extent, MIB-1 labeling index (LI), and PEA-15 expression level. Multivariable analyses revealed that high PEA-15 expression level displayed a significant correlation with longer overall survival (OS) in high-grade astrocytomas (P = 0.0024). Patients with total resection survived significantly longer (P = 0.0044) than those with lower resection extent, while patients with MIB-1 labeling index ≤25% indicated significant (P = 0.0434) correlation with OS as well. In conclusion, PEA-15 expression level was inversely associated with WHO grade and may serve as an important prognostic factor for high-grade astrocytomas.     

Cerebrospinal fluid stimulates leptomeningeal and meningioma cell proliferation and activation of STAT3

The role of cerebrospinal fluid (CSF) in the pathogenesis of meningiomas is unknown. Cell cultures from three human leptomeninges, five WHO grade I and seven grade II meningiomas were treated with remnant CSF from 22 patients with no central nervous system disease and normal cell indices. Cells were evaluated by CyQUANT for DNA synthesis/cell proliferation and by western blots for phosphorylation/activation of growth regulatory pathways activated in meningiomas including JAK1–STAT3, MEK1–p44/42MAPK, Akt–mTOR and Rb. Analysis of Caspase 3 activation and survivin was also performed. Finally, the effects of PDGF neutralizing antibody and cucurbitacin, a STAT3 inhibitor on CSF stimulation were tested. Compared to controls and the mitogen PDGF-BB, various CSF samples significantly stimulated DNA synthesis/cell proliferation in 20 and 22 week leptomeningeal cultures and all of the grade I and II meningioma cells tested. Collectively CSF samples, from multiple different patients, stimulated DNA synthesis in tests of 23 of 32 grade I and 18 of 28 grade II meningioma cells. CSF stimulated phosphorylation/activation of STAT3 and reduced p44/42 MAPK in the leptomeningeal, all three grade I and 1 of three grade II meningioma cells. CSF did not affect Caspase 3 activity or survivin levels. PDGF neutralizing antibody had no effect on CSF stimulation but cucurbitacin blocked PDGF and CSF stimulation. While there are limitations to the CSF available since they were not from “normal” volunteers, the studies suggest that, in some settings, CSF is potentially mitogenic to leptomeningeal and meningioma cells and may act, in part, via activation of STAT3.     

A role for the p53 pathway in the pathology of meningiomas with <Emphasis Type="Italic">NF2</Emphasis> loss

The neurofibromatosis 2 locus (NF2) is inactivated through mutation and loss of heterozygosity (LOH) in 40–65% of all sporadic meningiomas, while the role of the p53 tumor suppression pathway in meningioma initiation and progression is still unclear. This study aims to determine if a p53 codon 72 arginine-to-proline polymorphism, found to be correlated with cancer development and cancer patient survival in other tumors, is associated with sporadic meningioma initiation or progression. We investigated Pro72 incidence in a cohort of 92 sporadic meningiomas and analyzed its association with histological grade (WHO classification) and with NF2 LOH (determined using polymorphic microsatellite markers on 22q). The Pro72 allele was not found to be selected for in the cohort. However, in the subgroup of meningiomas with NF2 LOH and carrying Pro72, 50.0% had high grade tumors (WHO grades II and III) compared to only 14.3% of those without NF2 LOH (OR = 6.0, CI = 1.56–23.11, P = 0.012). The significant association occurred only when considering subgroups of meningiomas with or without NF2 LOH, suggesting that not including NF2 status when analyzing study cohorts may explain the variability seen in the literature where all meningiomas were grouped together. Our data suggests a role for the p53 pathway in the progression of meningiomas in which NF2 is inactivated, and highlights the importance of accounting for NF2 LOH in future studies of meningiomas and the p53 pathway.     

Preliminary experience of whole-brain radiation therapy (WBRT) in breast cancer patients with brain metastases previously treated with bevacizumab-based chemotherapy

We report our experience of bevacizumab-based chemotherapy (BBCT) followed by whole-brain radiation therapy (WBRT) for breast cancer (BC) patients (pts) with inoperable brain metastases (BM) or who refused surgery. This is a retrospective study of seven metastatic BC pts treated at the Institut Curie with at least one course of BBCT before WBRT, with a delay of ≤12 months between the two treatments. Toxicity was scored according to the common terminology criteria for adverse events (v4. 2010). Median age was 56 years (41–65). Median follow-up was 5.9 months (0.4–24.6). The median dose of bevacizumab was 10 mg/kg. Median number of cycles BBCT was six (5–17). Different chemotherapy regimens were used, the most common combination was paclitaxel–bevacizumab. WBRT was delivered in ten fractions, five fractions/week, for two weeks, to a total of 30 Gy. One pt underwent stereotactic radio surgery (SRS) after WBRT. No pt received BBCT during RT. Most common reported side-effects were nausea (n = 4), headache (n = 3), vomiting (n = 1), and vertigo (n = 3). All pts had mild or moderate grade ≤2 neurologic toxicity. There were no radiological signs of necrosis or cerebral ischemia. BBCT before WBRT was not associated with severe brain toxicity. Because of the limited number of pts, the different BBCT regimens, and important delays between treatments, these results must be confirmed prospectively.     

Intensity modulated radiation therapy or stereotactic fractionated radiotherapy for infratentorial ependymoma in children: a multicentric study

This study was to evaluate the treatment dosimetry, efficacy and toxicity of intensity modulated radiation therapy (IMRT) and fractionated stereotactic radiotherapy (FSRT) in the management of infratentorial ependymoma. Between 1999 and 2007, seven children (median age, 3.1 years) with infratentorial ependymoma were planned with either IMRT (3 patients) or SFRT (4 patients), the latter after conventional posterior fossa irradiation. Two children underwent gross total resection. Median prescribed dose was 59.4 Gy (range, 55.8–60). The median follow-up for surviving patients was 4.8 years (range, 1.3–8). IMRT (median dose, 59.4 Gy) and FSRT (median dose, 55.8 Gy) achieved similar optimal target coverage. Percentages of maximum doses delivered to the cochleae (59.5 vs 85.0% Gy; P = 0.05) were significantly inferior with IMRT, when compared to FSRT planning. Percentages of maximum doses administered to the pituitary gland (38.2 vs 20.1%; P = 0.05) and optic chiasm (38.1 vs 14.1%; P = 0.001) were, however, significantly higher with IMRT, when compared to FSRT planning. No recurrences were observed at the last follow-up. The estimated 3-year progression-free survival and overall survival were 87.5 and 100%, respectively. No grade >1 acute toxicity was observed. Two patients presented late adverse events (grade 2 hypoacousia) during follow-up, without cognitive impairment. IMRT or FSRT for infratentorial ependymomas is effective and associated with a tolerable toxicity level. Both treatment techniques were able to capitalize their intrinsic conformal ability to deliver high-dose radiation. Larger series of patients treated with these two modalities will be necessary to more fully evaluate these delivery techniques.     

Is there a place for low-dose chest and prophylactic brain irradiation in limited-disease small cell lung cancer

The aim of the study is to evaluate the outcome of low-dose bifractionated up-front radiotherapy (RT) followed by chemotherapy (CHT) in limited-disease small cell lung cancer (LD-SCLC). From December 1999 to February 2002, 20 LD-SCLC consecutive patients were treated by initial involved-field thoracic irradiation of 2 Gy twice daily to a total dose of 20 Gy, and concomitant prophylactic cranial irradiation (PCI) of 1.8 Gy twice daily to a total dose of 18 Gy followed 3 days later by 4–6 cycles of CHT with cisplatin and etoposide. Median follow-up was 66 months (52–77). There were no Grade 3–4 esophagitis or pneumonitis. Response rate was 90%, 45% of the patients showing a complete and 45% a partial response. Median time to first event was 13 months. Forty percent showed local infield recurrence, while 55% presented distant metastasis, 4 of them in the brain. Median survival time was 28 months. The Kaplan–Meier 1-, 3-, and 5-years survival rates were 95%, 35%, and 21%, respectively. Salvage RT was applied for local recurrence in 7 patients and for distant metastasis in 7 patients. The rate of brain recurrence with up-front low-dose PCI is favorable and should be further evaluated. Although the response and survival rates are promising, the high number of local recurrences indicates that the irradiation dose is insufficient for patients whose disease can be encompassed within a radical radiation portal.     

Feasibility and toxicity of combined photon and carbon ion radiotherapy for locally advanced adenoid cystic carcinomas

PURPOSE: To investigate clinical feasibility and toxicity of combined photon and carbon ion radiotherapy in locally advanced adenoid cystic carcinomas (ACC) within a prospective Phase I/II trial. METHODS AND MATERIALS: Between September 1998 and April 2002, 16 patients with histopathologically proven ACC and residual macroscopic tumor were treated with combined photon RT and a carbon ion boost to the macroscopic tumor. Median total tumor dose within the gross tumor volume (GTV) was 72 GyE. Photon radiation therapy (RT) consisted of fractionated stereotactic RT in 7 patients; 9 patients received stereotactic intensity-modulated RT. Carbon ion boost was delivered by intensity-controlled raster scanning at the heavy ion synchrotron (SIS) at the Heavy Ion Research Center (GSI) in Darmstadt. RESULTS: Median follow-up was 12 months. Three patients developed locoregional recurrences 9, 11, and 24 months after RT, respectively. Actuarial local control rates were 80.8% and 64.6% at 1 and 3 years, respectively. Overall survival rates were 100% and 83.3% at 1 and 3 years, respectively. Acute side effects greater than Common Toxicity Criteria (CTC) Grade 2 were observed in 2 patients; no patient developed late effects > CTC Grade 2. CONCLUSIONS: Combined photon and carbon ion RT is feasible and effective in patients with locally advanced ACC. Acute and late toxicity is moderate with respect to the delivered tumor doses and in accordance with the radiobiologic modeling. A Phase III trial is designed.     

uPA/PAI-1 expression and uPA promoter methylation in meningiomas

The extent of resection and the intrinsic biological aggressiveness of the tumor have been repeatedly identified as the primary determinants of meningioma recurrence. Invasive growth limits the resectability of meningiomas. Tumor invasion is mediated by matrix metalloproteases and their inhibitors such as uPA and PAI-1. In some cancers uPA expression is controlled in part by promoter methylation. In the work reported in this paper we investigated the role of uPA/PAI-1 expression and methylation of the uPA promoter in meningiomas. Sixty-five tumor tissue samples (WHO grade I: 26, grade II: 27, grade III: 12) from 58 patients were analyzed for uPA and PAI-1 protein content using a commercially available ELISA kit. For uPA promoter methylation analysis, a 365-bp promoter fragment was amplified by PCR after bisulfite treatment and subjected to a methylation-sensitive restriction digest with AciI. Pertinent clinical data were retrieved from the patients’ charts. uPA and PAI-1 protein expression correlated significantly with WHO grade (uPA: P < 0.033, PAI-1: P < 0.001). High (>6 ng/ml = median) PAI-1 levels were seen more frequently in tumors with brain invasion (P = 0.006) and proved a significant predictor of the patients’ prognosis (Kaplan–Meier estimates of progression-free survival: P = 0.004). Increased methylation of the uPA promoter was found to correlate significantly with lower levels of uPA expression. Our data suggest PAI-1 (and possibly to a lesser degree uPA) as potential prognostic markers in meningiomas. uPA expression in meningiomas might, in part, be controlled by promoter methylation.     

Feasibility of adequate resectable rectal cancer treatment in a third-level hospital

Purpose  The aim of this study was to determine the feasibility, concerning compliance to protocol and recommended clinical practice guidelines, as well as efficacy results of multidisciplinary treatment (surgery, radiotherapy and chemotherapy) of resectable rectal cancer in a third-level hospital devoid of radiotherapy and clinical oncology units. Patients and methods  A retrospective, single-institution analysis was completed for 45 consecutive patients diagnosed with resectable rectal cancer who entered an officially proposed multidisciplinary treatment protocol from October 1998 to September 2003. Adequacy of patient inclusion, according to clinical stage, was reviewed. Neoadjuvant radiotherapy schedule, surgery procedures and adjuvant chemotherapy indication were assessed. All treatment time intervals were analysed. Finally, efficacy results are discussed and contextualised by comparison with results of clinical trials which support this treatment strategy. Results  According to an independent board review, 3 patients (6.7%) with stage I rectal cancer, 31 patients (68.9%) with stage II and 11 patients (24.4%) with stage III rectal cancer were included. Radiotherapy dosage, volume and schedule were as planned. Median time from diagnosis to start of radiotherapy was 26.36 days (24.26–28.57; CI 95%). Median duration of radiotherapy was 6.00 days (5.56–6.44; CI 95%). Median time from start of radiotherapy to surgery was 15.67 days (14.47–16.87; CI 95%). Median time from completion of radiotherapy to surgery was 10.67 days (9.53–11.81; CI 95%). Most of the patients underwent low anterior resection [23 patients (51.2%)] and abdominoperineal resection [16 patients (35.6%)]. Correlation between clinical and pathologic staging was as expected. Twenty-nine patients (64.4%) of the 45 that were initially included started adjuvant chemotherapy. A statistically significant relationship between pathologic stage (grouped I–II vs. III) and the use of adjuvant chemotherapy was found (p=0.033; chi-square test). Radiotherapy- and chemotherapy-induced toxicity did not differ from that previously reported. With a median follow-up of 65.46 months, a total of 10 recurrences have been diagnosed, all of them in stage III patients. Overall survival rate at five years was 76% for the complete population included. Conclusion  Multidisciplinary treatment of resectable rectal cancer in a third-level hospital is feasible. Although efficacy results are comparable to those previously reported in the literature, further improvements in clinical staging as well as in adjuvant chemotherapy indication are desirable.