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Introduction: Long-term data on outcomes of operable stage III NSCLC are scarce. Methods: Individual patient data from 368 patients enrolled in one phase III and two phase II trials were pooled and outcomes after applying the eighth (denoted with an asterisk [*]) versus the sixth TNM staging edition were compared. Patients were treated with either preoperative radiotherapy following 3 cycles of induction chemotherapy (trimodal) or neoadjuvant chemotherapy alone (bimodal). Results: With the sixth version, the 5- and 10-year survival rates were 38% and 28% for stage IIIA, respectively, and 36% and 24% for stage IIIB, respectively. Factors associated with improved 5-year overall survival were younger age, R0 resection, and pathologic complete remission (pCR) (p = 0.043, p < 0.001 and p = 0.009). With the eighth TNM staging version, 162 patients were moved from stage IIIA to IIIB*. The 5- and 10-year survival rates were 41% and 29% for stage IIIA*, respectively, and 35% and 27% for stage IIIB* patients, respectively. There was no difference in the bi- versus trimodal group with regard to median overall survival (28 months [95% confidence interval (CI): 21-39 months] and 37 months [95% CI: 24-51 months], p = 0.9) and event-free survival (12 months [95% CI: 9-15 months] versus 13 months [95% CI: 10-22 months], p = 0.71). Conclusions: We showed favorable 10-year survival rates of 29% and 27% in stage IIIA* and IIIB*, respectively. Younger age, R0 resection, and pathologic complete response were associated with improved long-term survival. Outcomes using the sixth versus eighth edition of the TNM classification were similar in operable stage III NSCLC.

BACKGROUND: Following maximal safe resection, radiation (RT) with concurrent and 6 cycles (C) of adjuvant temozolomide (TMZ) [Stupp NEJM 2005] has been established as standard of care for newly-diagnosed glioblastoma (GBM). This regimen has been adopted with variations, including extending TMZ beyond 6 cycles. The optimal duration of maintenance therapy remains a matter of debate. OBJECTIVES: Compare outcomes of patients who completed 6C of TMZ and discontinued treatment to those of patients who continued TMZ >6C. METHODOLOGY: We performed a pooled analysis of 4 randomized trials (EORTC/NCIC 26981-CE.3; EORTC26071-CENTRIC; EMD-CORE; RTOG 0525-Intergroup). All patients received the standard of care (TMZ/RT with TMZ). All patients who completed TMZ 6C and had not progressed within 28 days were included. Based on local practice and the discretion of the investigator TMZ could be continued for up to 12C. Patients were grouped into those who completed 6C TMZ and those who continued >6C; progression-free and overall survival were analyzed, adjusted by age, performance status, resection extent, and MGMT status. Exploratory analyses with and without MGMT data imputation were performed at 5% significance. RESULTS: Independent of evaluated prognostic factors, treatment with >6C TMZ was significantly associated with improved PFS [HR 0.77 (0.61-0.97), p = 0.03]. This effect was more pronounced in patients with methylated MGMT [HR 0.64 (0.47-0.88), p 6C groups were well-balanced, except MGMT methylation status; methylated status was less frequent in patients receiving >6C (39% vs 62%). Prognostic factors including age, MGMT methylation, extent of resection, and performance status had an expected impact on outcomes. CONCLUSION: Increasing the number of cycles of TMZ beyond 6 months is not shown to increase OS. PFS was improved, more so in patients with MGMT-methylated tumors.

Background Complete resection of locally advanced sigmoid colon cancer (LASCC) is sometimes difficult. Patients with LASCC have a dismal prognosis and poor quality of life, which has encouraged the evaluation of alternative multimodality treatments. This prospective study aimed to assess the feasibility and efficacy of neoadjuvant chemoradiotherapy (neoCRT) followed by surgery as treatment of selected patients with unresectable LASCC. Methods We studied the patients with unresectable LASCC who received neoCRT followed by surgery between October 2010 and December 2012. The neoadjuvant regimen consisted of external-beam radiotherapy to 50 Gy and capecitabine-based chemotherapy every 3 weeks. Surgery was scheduled 6–8 weeks after radiotherapy. Results Twenty-one patients were included in this study. The median follow-up was 42 months (range, 17–57 months). All patients completed neoCRT and surgery. Resection with microscopically negative margins (R0 resection) was achieved in 20 patients (95.2%). Pathologic complete response was observed in 8 patients (38.1%). Multivisceral resection was necessary in only 7 patients (33.3%). Two patients (9.5%) experienced grade 2 postoperative complications. No patients died within 30 days after surgery. For 18 patients with pathologic M0 (ypM0) disease, the cumulative probability of 3-year local recurrence-free survival, disease-free survival and overall survival was 100.0%, 88.9% and 100.0%, respectively. For all 21 patients, the cumulative probability of 3-year overall survival was 95.2% and bladder function was well preserved. Conclusion For patients with unresectable LASCC, preoperative chemoradiotherapy and surgery can be performed safely and may result in an increased survival rate.

This study seeks to perform a survey of patterns of practice among the different physicians involved in the bone metastases management, with special focus on external beam radiotherapy (EBRT).A questionnaire about bone metastases based on clinical cases and supplemented with general questions, including medical therapies, EBRT and metabolic radiotherapy strategies, surgery, and supportive care approaches, was sent to 4,706 French-speaking physicians in Belgium, France, Luxemburg, and Switzerland.Overall, 644 questionnaires were analyzed. Twenty-eight percent concerned the radiotherapy approach and were judged adequate to respond to the part dedicated to EBRT. Sixty-nine percent of physicians used a total dose irradiation of 30 Gy delivered in ten fractions. A large majority (75%) used two opposed fields prescribed at mid-depth (30%), or with non-equally weighted fields (45%). Seventy percent irradiated also above and below the concerned vertebra. A dosimetry planning treatment was done in 85% and high-energy megavoltage photons were used in 42%. Moreover, 54% physicians used short course radiotherapy in routine.Radiotherapy remains the mainstay of treatment of bone metastases, but there is substantial heterogeneity in clinical practice. Guidelines and treatment protocols are required to improve the treatment quality.

Background: Glioblastoma is a highly vascularised tumour with a high expression of both vascular endothelial growth factor (VEGF) and VEGFR. PTK787/ZK222584 (PTK/ZK, vatalanib), a multiple VEGF receptor inhibitor, blocks the intracellular tyrosine kinase activity of all known VEGF receptors and is therefore suitable for long-term therapy of pathologic tumour neovascularisation. Patients and methods: The study was designed as an open-label, phase I/II study. A classic 3 + 3 design was selected. PTK/ZK was added to standard concomitant and adjuvant treatment, beginning in the morning of day 1 of radiotherapy (RT), and given continuously until disease progression or toxicity. PTK/ZK doses started from 500 mg with subsequent escalations to 1000 and 1250 mg/d. Adjuvant or maintenance PTK after the end of radiochemotherapy was given at a previously established dose of 750 mg twice daily continuously with TMZ at the standard adjuvant dose. Results: Twenty patients were enrolled. Dose-limiting toxicities at a once daily dose of 1250 mg were grade 3 diarrhoea (n = 1), grade 3 ALT increase (n = 2), and myelosuppression. with grade 4 thrombocytopenia and neutropenia (n = 1). The recommended dose of PTK/ZK in combination with radiotherapy and temozolomide (TMZ) is 1000 mg once a day. This treatment is safe and well tolerated. Conclusion: In our phase I study once daily administration of up to 1000 mg of PTK/ZK in conjunction with concomitant temozolomide and radiotherapy was feasible and safe. Prolonged administration of this oral agent is manageable. The planned randomised phase II trial was discontinued right at its onset due to industry decision not to further develop this agent. (C) 2009 Elsevier Ltd. All rights reserved.

AimsThe psychometric properties of the EORTC QLQ-BN20, a brain cancer-specific HRQOL questionnaire, have been previously determined in an English-speaking sample of patients. This study examined the validity and reliability of the questionnaire in a multi-national, multi-lingual study.MethodsQLQ-BN20 data were selected from two completed phase III EORTC/NCIC clinical trials in brain cancer (N = 891), including 12 languages. Experimental treatments were surgery followed by radiotherapy (RT) and adjuvant PCV chemotherapy or surgery followed by concomitant RT plus temozolomide (TMZ) chemotherapy and adjuvant TMZ chemotherapy. Standard treatment consisted of surgery and postoperative RT alone. The psychometrics of the QLQ-BN20 were examined by means of multi-trait scaling analyses, reliability estimation, known groups validity testing, and responsiveness analysis.ResultsAll QLQ-BN20 items correlated more strongly with their own scale (r > 0.70) than with other QLQ-BN20 scales. Internal consistency reliability coefficients were high (all α 0.70). Known-groups comparisons yielded positive results, with the QLQ-BN20 distinguishing between patients with differing levels of performance status and mental functioning. Responsiveness of the questionnaire to changes over time was acceptable.ConclusionThe QLQ-BN20 demonstrates adequate psychometric properties and can be recommended for use in conjunction with the QLQ-C30 in assessing the HRQOL of brain cancer patients in international studies.

Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFR(amp)), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, we used the clinical data and tumor samples of the patients included in multicenter prospective phase III European Organisation for Research and Treatment of Cancer (EORTC) study 26951 on the effects of adjuvant procarbazine, chloroethyl cyclohexylnitrosourea (lomustine), and vincristine chemotherapy in anaplastic oligodendroglial tumors. Fluorescence in situ hybridization was used to assess copy number aberrations of chromosome 1p, 19q, 7, 10, and 10q and EGFR. Three different analyses were performed: on all included patients based on local pathology diagnosis, on the patients with confirmed anaplastic oligodendroglial tumors on central pathology review, and on this latter group but after excluding anaplastic oligoastrocytoma (AOA) with necrosis. As a reference set for glioblastoma multiforme (GBM), patients from the prospective randomized phase III study on GBM (EORTC 26981) were used as a benchmark. In 257 of 368 patients, central pathology review confirmed the presence of an anaplastic oligodendroglial tumor. Tumors with combined 1p and 19q loss (1p(loss)19q(loss)) were histopathologically diagnosed as anaplastic oligodendroglioma, were more frequently located in the frontal lobe, and had a better outcome. Anaplastic oligodendroglial tumors with EGFR amp were more frequently AOA, were more often localized outside the frontal lobe, and had a survival similar to that for GBM. Survival of patients with AOA harboring necrosis was in a similar range as for GBM, while patients with AOA with only endothelial proliferation had better overall survival. In univariate analyses, all molecular factors except loss of 10q were of prognostic significance, but on multivariate analysis a histopathological diagnosis of AOA, necrosis, and 1p(loss)19q(loss) remained independent prognostic factors. AOA tumors with necrosis are to be considered WHO grade IV tumors (GBM). Of all molecular markers analyzed in this study, especially loss of 1p/19q carried prognostic significance, while the others contributed little prognostic value to classical histology. Neuro-Oncology 11, 737-746, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00260, February 17, 2009. URL http://neuro-oncology.dukeiournals.org; DOI: 10.1215/15228517-2009-011)

BACKGROUND: Stage IIIB non-small-cell lung cancer (NSCLC) is usually thought to be unresectable, and is managed with chemotherapy with or without radiotherapy. However, selected patients might benefit from surgical resection after neoadjuvant chemotherapy and radiotherapy. The aim of this multicentre, phase II trial was to assess the efficacy and toxicity of a neoadjuvant chemotherapy and radiotherapy followed by surgery in patients with technically operable stage IIIB NSCLC. METHODS: Between September, 2001, and May, 2006, patients with pathologically proven and technically resectable stage IIIB NSCLC were sequentially treated with three cycles of neoadjuvant chemotherapy (cisplatin with docetaxel), immediately followed by accelerated concomitant boost radiotherapy (44 Gy in 22 fractions) and definitive surgery. The primary endpoint was event-free survival at 12 months. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030810. FINDINGS: 46 patients were enrolled, with a median age of 60 years (range 28-70). 13 (28%) patients had N3 disease, 36 (78%) had T4 disease. All patients received chemotherapy; 35 (76%) patients received radiotherapy. The main toxicities during chemotherapy were neutropenia (25 patients [54%] at grade 3 or 4) and febrile neutropenia (nine [20%]); the main toxicity after radiotherapy was oesophagitis (ten patients [29%]; nine grade 2, one grade 3). 35 patients (76%) underwent surgery, with pneumonectomy in 17 patients. A complete (R0) resection was achieved in 27 patients. Peri-operative complications occurred in 14 patients, including two deaths (30-day mortality 5.7%). Seven patients required a second surgical intervention. Pathological mediastinal downstaging was seen in 11 of the 28 patients who had lymph-node involvement at enrolment, a complete pathological response was seen in six patients. Event-free survival at 12 months was 54% (95% CI 39-67). After a median follow-up of 58 months, the median overall survival was 29 months (95% CI 16.1-NA), with survival at 1, 3, and 5 years of 67% (95% CI 52-79), 47% (32-61), and 40% (24-55). INTERPRETATION: A treatment strategy of neoadjuvant chemotherapy and radiotherapy followed by surgery is feasible in selected patients. Toxicity is considerable, but manageable. Survival compares favourably with historical results of combined treatment for less advanced stage IIIA disease. FUNDING: Swiss Group for Clinical Cancer Research (SAKK) and an unrestricted educational grant by Sanofi-Aventis (Switzerland).

PURPOSE: To retrospectively analyze and assess the outcomes and prognostic factors in a large number of patients with atypical and malignant meningiomas. METHODS AND MATERIALS: Ten academic medical centers participating in this Rare Cancer Network contributed 119 cases of patients with atypical or malignant meningiomas treated with external beam radiotherapy (EBRT) after surgery or for recurrence. Eligibility criteria were histologically proven atypical or anaplastic (malignant) meningioma (World Health Organization Grade 2 and 3) treated with fractionated EBRT after initial resection or for recurrence, and age >18 years. Sex ratio (male/female) was 1.3, and mean (+/-SD) age was 57.6 +/- 12 years. Surgery was macroscopically complete (Simpson Grades 1-3) in 71% of patients; histology was atypical and malignant in 69% and 31%, respectively. Mean dose of EBRT was 54.6 +/- 5.1 Gy (range, 40-66 Gy). Median follow-up was 4.1 years. RESULTS: The 5- and 10-year actuarial overall survival rates were 65% and 51%, respectively, and were significantly influenced by age >60 years (p = 0.005), Karnofsky performance status (KPS) (p = 0.01), and high mitotic rate (p = 0.047) on univariate analysis. On multivariate analysis age >60 years (p = 0.001) and high mitotic rate (p = 0.02) remained significant adverse prognostic factors. The 5- and 10-year disease-free survival rates were 58% and 48%, respectively, and were significantly influenced by KPS (p = 0.04) and high mitotic rate (p = 0.003) on univariate analysis. On multivariate analysis only high mitotic rate (p = 0.003) remained a significant prognostic factor. CONCLUSIONS: In this multicenter retrospective study, age, KPS, and mitotic rate influenced outcome. Multicenter prospective studies are necessary to clarify the management and prognostic factors of such a rare disease.

To evaluate the outcome of patients with carcinoma of anal margin in terms of recurrence, survival, and radiation toxicity. A series of 45 consecutive patients, with anal margin carcinoma treated between 1983 and 2006 with curative intent at two institutions, was retrospectively analyzed. A surgical excision (close or positive surgical margin in 22 out of 29 patients) was realized before radiotherapy (RT). RT consisted of definitive external beam RT (EBRT) in 36 patients, brachytherapy (BT) alone in two patients, and both BT and EBRT in seven patients. The median total radiation dose was 59.4 Gy (range, 30–74 Gy). The 5-year locoregional control (LRC) rate was 78% [95% confidence interval (CI), 64–93%]. The 5-year disease-specific survival (DSS) and overall survival (OS) rates were respectively 86% (95% CI, 72–99%) and 55% (95% CI, 44–66%). The overall anal conservation rate was 80% for the whole series. There was no significant association between local recurrence and patient age, histological grade, tumor size, T stage, overall treatment time, RT dose, or chemotherapy. Long-term side effects were observed in 15 patients (33%). Only three patients developed grade 3–4 late toxicity (CTCAE/NCI v3.0). Significant relationship was found between dose, and complication rate (48% for dose ≥59.4 Gy versus 8% for dose

Summary Background A randomised trial published by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group (trial 26981-22981/CE.3) showed that addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma significantly improved survival. We aimed to undertake an exploratory subanalysis of the EORTC and NCIC data to confirm or identify new prognostic factors for survival in adult patients with glioblastoma, derive nomograms that predict an individual patient's prognosis, and suggest stratification factors for future trials. Methods Data from 573 patients with newly diagnosed glioblastoma who were randomly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this subanalysis. Survival modelling was done in three patient populations: intention-to-treat population of all randomised patients (population 1); patients assigned temozolomide and radiotherapy (population 2, n=287); and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection (population 3, n=103). Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase ( MGMT ) promoter methylation status. Nomograms were developed to predict an individual patient's median and 2-year survival probabilities. No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new standard of care. Findings Independent of the MGMT promoter methylation status, analysis in all randomised patients (population 1) identified combined treatment with temozolomide, more extensive tumour resection, younger age, Mini-Mental State Examination (MMSE) score of 27 or higher, and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome. In patients assigned temozolomide and radiotherapy (population 2), younger age, better performance status, more extensive tumour resection, and MMSE score of 27 or higher were associated with better survival. In patients who had tumours resected, who were assigned temozolomide and radiotherapy, and who had available MGMT promoter methylation status (population 3), methylated MGMT , better performance status, and MMSE score of 27 or higher were associated with improved survival. Nomograms were developed and are available at http://www.eortc.be/tools/gbmcalculator. Interpretation MGMT promoter methylation status, age, performance status, extent of resection, and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma. Stratifying by MGMT promoter methylation status should be mandatory in all glioblastoma trials that use alkylating chemotherapy. Nomograms can be used to predict an individual patient's prognosis, and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management.

Amongst skull base tumors, chordomas (CHOR), chondrosarcomas (CS), and paragangliomas (PGLs) represent major therapeutic challenges. For CHOR and CS, even maximally safe surgery is followed by a high rate of local recurrence or progression. Thus high-dose, high-precision radiotherapy needs to be given postoperatively, and this is well accomplished by particle therapy. With proton beam radiotherapy (PBT), local control rates are good for CHOR and excellent for CS, with a limited risk of complications. Therefore PBT is often considered to be the standard treatment for these tumors. However postoperative RS and STRT are also able to deliver safely high-dose radiotherapy to CHOR and CS. Results demonstrate that they can yield good to excellent local control rates, and in the absence of PBT they can reasonably be used as alternative therapeutic approaches. In large tumors, where RS may be followed by an increased risk of complications, STRT, which combines the precision of RS and the biological advantage of fractionation, should be preferred. Like for CHOR and CS, a genuine complete resection is rarely possible for PGL, or at the sacrifice of cranial nerves. Conformal, fractionated external beam radiotherapy with moderate-to-high doses is followed by an excellent long-term local control. As PGLs are slow-growing tumors, they shrink also slowly and thus local control after radiotherapy should be defined as the absence of clinical or radiological progression. Results after RS and STRT are also excellent, but like for CHOR and CS, STRT is preferred in case of large tumors.

Summary Background One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. Methods We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m 2 cisplatin and 85 mg/m 2 docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. Findings From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7–22·9) in the chemoradiotherapy group and 11·6 months (8·4–15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6–50·0) with radiotherapy, compared with 26·2 months (19·9–52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. Interpretation Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. Funding Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

The aim of this study was to assess the outcome in patients with cerebellar glioblastoma (GBM) treated in 15 institutions of the Rare Cancer Network.Data from a series of 45 adult patients with cerebellar GBM were collected in a retrospective multicenter study. Median age was 50.3 years. Brainstem invasion was observed in 9 (20%) patients. Radiotherapy (RT) was administered to 36 patients (with concomitant chemotherapy, 7 patients). Adjuvant chemotherapy after RT was administered in 8 patients. Median RT dose was 59.4 Gy. Median follow-up was 7.2 months (range, 3.4-39.0).The 1-year and 2-year actuarial overall survival rate was 37.8% and 14.7%, respectively, and was significantly influenced by salvage treatment (p = 0.048), tumor volume (p = 0.044), extent of neurosurgical resection (p = 0.019), brainstem invasion (p = 0.0013), additional treatment after surgery (p0.001), and completion of the initial treatment (p0.001) on univariate analysis. All patients experienced local progression: 8 and 22 had progression with and without a distant failure, respectively. The 1- and 2-year actuarial progression free survival was 25% and 10.7%, respectively, and was significantly influenced by brainstem invasion (p = 0.002), additional treatment after surgery (p = 0.0016), and completion of the initial treatment (p0.001). On multivariate analysis, survival was negatively influenced by the extent of surgery (p = 0.03) and brainstem invasion (p = 0.02).In this multicenter retrospective study, the observed pattern of failure was local in all cases, but approximately 1 patient of 4 presented with an extracerebellar component. Brainstem invasion was observed in a substantial number of patients and was an adverse prognostic factor.

Purpose: Predicting late effects in patients treated with radiation therapy by assessing in vitro radiation-induced CD4 and CD8 T-lymphocyte apoptosis can be useful in individualizing treatment. Experimental Design: In a prospective study, 399 curatively irradiated patients were tested using a rapid assay where fresh blood samples were in vitro irradiated with 8 Gy X-rays. Lymphocytes were collected and prepared for flow cytometric analysis. Apoptosis was assessed by associated condensation of DNA. The incidences of late toxicities were compared for CD4 and CD8 T-lymphocyte apoptoses using receiver-operating characteristic curves and cumulative incidence. Results: No association was found between early toxicity and T-lymphocyte apoptosis. Grade 2 and 3 late toxicities were observed in 31% and 7% of patients, respectively. More radiation-induced T-lymphocyte apoptosis was significantly associated with less grade 2 and 3 late toxicity (Gray's test, P < 0.0001). CD8 (area under the curve = 0.83) was more sensitive and specific than CD4. No grade 3 late toxicity was observed for patients with CD4 and CD8 values greater than 15% and 24%, respectively. The 2-year cumulative incidence for grade 2 or 3 late toxicity was 70%, 32%, and 12% for patients with absolute change in CD8 T-lymphocyte apoptosis of ≤16, 16 to 24, and >24, respectively. Conclusions: Radiation-induced T-lymphocyte apoptosis can significantly predict differences in late toxicity between individuals. It could be used as a rapid screen for hypersensitive patients to radiotherapy. In future dose escalation studies, patients could be selected using the apoptosis assay.

BACKGROUND: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. RESULTS: The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P

Background and purpose : To assess the feasibility and efficacy of accelerated 66-Gy postoperative radiotherapy (PORT) using a single-fraction regimen from Mondays to Thursdays and a concomitant boost on Friday afternoon sessions in patients with locally advanced head and neck cancer (LAHNC). Patients and methods : Between December 1997 and June 2002, 89 consecutive patients with pT1–pT4 and/or pN0–pN3 LAHNC were included. PORT was indicated in patients with positive surgical margins, T4 tumors, or extracapsular nodal infiltration. RT consisted of 66Gy (2Gy/fr) in 5 weeks and 3 days. Median follow-up was 21 months (range 2–59). Results : Acute morbidity was acceptable: grade 3 mucositis in 20 (22%) patients, grade 3 dysphagia in 22 (25%) patients, and grade 3 skin erythema in 18 (20%) patients. Median weight loss was 2 kg (range 0–14.5). No grade 4 toxicity was observed. Late effects included grade 3 xerostomia in 6 (7%) patients, and grade 3 edema in 2 (2%) patients. Median time to locoregional relapse was 10 months (range 2–21). Two-year overall, cause-specific, and disease-free survival rates were 70% (95% confidence interval (CI) 59–81), 75% (95% CI 64–86), and 63% (95% CI 52–74), respectively. The 2-year actuarial locoregional control rate was 80% (95% CI 70–90). Distant metastasis probability at 4 years was 38% (95% CI 20–56). Multivariate analysis revealed that pT-classification (pT1–2 vs. pT3–4) and extranodal extension (0, 1 vs. 2 or more) were the two factors independently influencing the outcome. Conclusions : We conclude that reducing the overall treatment time using an accelerated PORT schedule including a once-weekly concomitant boost (six fractions per week) is easily feasible with excellent local control. Acute and late RT-related morbidity is acceptable. Given the disease progression pattern (distant metastases), adjuvant chemotherapy should be considered.

Although postoperative radiotherapy (RT) is widely used in patients with low-grade gliomas (LGGs), its clinical benefit remains unproven. Because LGGs include diseases with many different histologies, cytogenetic patterns, and natural histories, evaluating the effect of any treatment for LGGs is difficult. Analysis of prognostic subgroups has shown median survival rates ranging from 1 to 10 years. The clinical benefit of postoperative RT in LGGs in retrospective studies is confounded by the heterogeneity of LGGs and treatment-related variables. These studies report conflicting results, most likely because of differences in patient populations. The only prospective, randomized trial comparing postoperative RT with observation failed to show a survival benefit but showed a modest, although statistically significant, improvement in time to progression. Given that two thirds of patients in the observation group received RT at progression, the absence of a survival benefit suggests that RT is active in LGGs, but that delayed RT may provide the same survival advantage as postoperative RT. Moreover, high-dose or whole-brain RT can cause cognitive deficits. Our opinion is that postoperative RT should not be administered routinely to patients with LGGs. If RT is deemed necessary, such as in progressive or inoperable disease causing neurologic symptoms, a total dose of ≤50 Gy with a fractional dose of ≤1.8 to 2 Gy should be administered using modern, highly conformal techniques. Ideally, RT should be used only within the context of clinical research protocols.

Purpose: To assess the outcome and prognostic factors in patients with orbital lymphoma treated by radiotherapy (RT). Methods and Materials: Between 1980 and 1999, 90 consecutive patients with primary orbital lymphoma were treated in 13 member institutions of the Rare Cancer Network. A full staging workup was completed in 56 patients. Seventy-eight patients had low-, 6 intermediate-, and 6 high-grade lymphoma, and 75 had a single orbital localization. All patients underwent RT with a median dose of 34.2 Gy (range 4.0–50.4). Eleven patients received chemotherapy in addition to RT. Results: After RT, local control was achieved in 97% of the patients. Local progression occurred in 2% and local relapse 1%. The rate of systemic relapse was 20%, and 9% of the patients developed metachronous contralateral eye involvement. The 5-year disease-free survival, overall survival, and cause-specific survival rate was 65%, 78%, and 87%, respectively. In univariate analyses, the statistically significant favorable prognostic factors were younger age, low grade, normal erythrocyte sedimentation rate, absence of muscular infiltration, complete response to treatment, conjunctival localization, and normal lactate dehydrogenase value for overall survival, disease-free survival, and freedom from treatment failure. In multivariate analysis, the favorable factors were younger age and low grade for overall and disease-free survival; a favorable response, conjunctival localization, and complete staging were highly significant for disease-free survival and freedom from treatment failure. Neither the RT technique nor the total dose influenced the outcome. Cataract and xerophthalmia were the most prominent late toxicities. Conclusion: Moderate- to low-dose RT alone is able to control primary orbital lymphoma with low morbidity. A full staging workup is warranted in these patients. Prognostic factors were identified that could be useful in the overall management of this uncommon site of primary lymphoma.

PURPOSE: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM. PATIENTS AND METHODS: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m2/d × 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy × 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m2/d × 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival. RESULTS: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome. CONCLUSION: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing.

The Rare Cancer Network (RCN) was formed in the early 1990's to create a global network that could pool knowledge and resources in the studies of rare malignancies whose infrequency prevented both their study with prospective clinical trials. To date, the RCN has initiated 74 studies resulting in 46 peer reviewed publications. The First International Symposium of the Rare Cancer Network took place in Nice in March of 2014. Status updates and proposals for new studies were heard for fifteen topics. Ongoing studies continue for cardiac sarcomas, thyroid cancers, glomus tumors, and adult medulloblastomas. New proposals were presented at the symposium for primary hepatic lymphoma, solitary fibrous tumors, Rosai-Dorfman disease, tumors of the ampulla of Vater, salivary gland tumors, anorectal melanoma, midline nuclear protein in testes carcinoma, pulmonarylymphoepithelioma-like carcinoma, adenoid cystic carcinoma of the trachea, osteosarcomas of the mandible, and extra-cranial hemangiopericytoma. This manuscript presents the abstracts of those proposals and updates on ongoing studies, as well a brief summary of the vision and future of the RCN. © M. Ozsahin et al. 2014. Licensee PAGEPress, Italy., SCOPUS: ar.j, info:eu-repo/semantics/published

Approximately, twenty years ago, the Rare Cancer Network (RCN) was formed in Lausanne, Switzerland, to support the study of rare malignancies. The RCN has grown over the years and now includes 130 investigators from twenty-four nations on six continents. The network held its first international symposium in Nice, France, on March 21-22, 2014. The proceedings of that meeting are presented in two companion papers. This manuscript reviews the history of the growth of the RCN and contains the abstracts of fourteen oral presentations made at the meeting of prior RCN studies. From 1993 to 2014, 74 RCN studies have been initiated, of which 54 were completed, 10 are in progress or under analysis, and 9 were stopped due to poor accrual. Forty-four peer reviewed publications have been written on behalf of the RCN.

The effect of hyaluronic acid (Ialugen cream) on acute skin reactions after radiotherapy, was assessed in a randomized, double-blind, placebo-controlled study.Out of the 152 patients presenting with head and neck, breast or pelvic carcinomas and registered in the study, 134 cases-70 in the Ialugen group (IA) and 64 in the placebo group (PBO)-completed their IA or PBO treatment. At the time of randomisation, these two groups were balanced for sex, age, weight and height. The mean total dose of radiation given during the study was 60.6 +/- 10.9 Gy in the IA group and 64.3 +/- 10.8 Gy in the PBO group (P = 0.47).Acute radio-epithelitis scores were significantly higher in the PBO group than in the IA group, starting from the control at week 3 and throughout the 6 weeks of treatment (P0.01 from week 3 to week 7; P0.05 at weeks 8 and 10). Likewise, the global efficacy judgement expressed, at the end of treatment, by both the physician and the patient showed a significant difference in favour of Ialugen (P0.01 and P0.05, respectively). There was no significant difference of tolerance between the IA and PBO treatments (P = 0.18 according to the physician and P = 0.42 from the patient's viewpoint).The prophylactic use of a cream with hyaluronic acid is shown to reduce the incidence of high grade radio-epithelitis, suggesting an interesting role of the hyaluronic acid cream as supportive treatment to improve compliance and quality of life in patients undergoing radiation therapy.

The potential of zalcitabine (ddC) to act as an ionizing radiation response modifier was tested on exponentially growing human cancer cells in vitro. Two human cell lines, WiDr (colon) and MCF-7 (breast) were exposed to ddC at 10 microM concentration for various lengths of time (18, 24, 48 and 72 h). On the WiDr cell line the dual effect of concentration and duration of exposure prior to irradiation was investigated. Experimental endpoints were clonogenicity and viability, as measured by colony formation assay (CFA) and MTT assay respectively. The impact on cell-cycle distribution prior to irradiation was assessed by flow cytometry using a double labeling technique (propidium iodide and bromodeoxyuridine pulse label). A significant reduction in surviving fraction and viability was observed for WiDr-cells irradiated after pre-exposure to 10 microM for 18, 48 and 72 h as compared to corresponding irradiated controls. At lower concentrations (1 and 5 microM), the radiosensitizing effect was only significant after a 72-h exposure (assessed by CFA). For MCF-7, ddC induced a significant modification of the dose response only with 24 and 48 h preincubation. However, the overall effect was less pronounced as compared to WiDr. Cell-cycle analysis showed accumulation in S-phase, 48 and 72 h after treatment with 10 microM ddC in the WiDr cells, with a progressive shift to late S-phase as shown by the biparametric analysis. The degree of radiosensitization is cell-line dependent with the most important sensitization observed on the most "radioresistant cell line", i.e., the cell line with the lowest alpha value and highest SF 2 (WiDr). For WiDr, radiosensitization by ddC depends on the duration of exposure and the concentration of the drug.

Over the past decade a series of trials of the EORTC Brain Tumor Group (BTG) has substantially influenced and shaped the standard-of-care of primary brain tumors. All these trials were coupled with biological research that has allowed for better understanding of the biology of these tumors. In glioblastoma, EORTC trial 26981/22981 conducted jointly with the National Cancer Institute of Canada Clinical Trials Group showed superiority of concomitant radiochemotherapy with temozolomide over radiotherapy alone. It also identified the first predictive marker for benefit from alkylating agent chemotherapy in glioblastoma, the methylation of the O6-methyl-guanyl-methly-transferase (MGMT) gene promoter. In another large randomized trial, EORTC 26951, adjuvant chemotherapy in anaplastic oligodendroglial tumors was investigated. Despite an improvement in progression-free survival this did not translate into a survival benefit. The third example of a landmark trial is the EORTC 22845 trial. This trial led by the EORTC Radiation Oncology Group forms the basis for an expectative approach to patients with low-grade glioma, as early radiotherapy indeed prolongs time to tumor progression but with no benefit in overall survival. This trial is the key reference in deciding at what time in their disease adult patients with low-grade glioma should be irradiated. Future initiatives will continue to focus on the conduct of controlled trials, rational academic drug development as well as systematic evaluation of tumor tissue including biomarker development for personalized therapy. Important lessons learned in neurooncology are to dare to ask real questions rather than merely rapidly testing new compounds, and the value of well designed trials, including the presence of controls, central pathology review, strict radiology protocols and biobanking. Structurally, the EORTC BTG has evolved into a multidisciplinary group with strong transatlantic alliances. It has contributed to the maturation of neurooncology within the oncological sciences.

The Rare Cancer Network (RCN), founded in 1993, performs research involving rare tumors that are not common enough to be the focus of prospective study. Over 55 studies have either been completed or are in progress. The aim of the paper is to present an overview of the 30 studies done through the RCN to date, organized by disease site. Five studies focus on breast pathology, including sarcoma, lymphoma, phyllodes tumor, adenoid cystic carcinoma, and ductal carcinoma in situ in young women. Three studies on prostate cancer address prostatic small cell carcinoma and adenocarcinoma of young and elderly patients. Six studies on head and neck cancers include orbital and intraocular lymphoma, mucosal melanoma, pediatric nasopharyngeal carcinoma, olfactory neuroblastoma, and mucosa-associated lymphoid tissue lymphoma of the salivary glands. There were 4 central nervous system studies on patients with cerebellar glioblastoma multiforme, atypical and malignant meningioma, spinal epidural lymphoma and myxopapillary ependymoma. Outside of these disease sites, there is a wide variety of other studies on tumors ranging from uterine leiomyosarcoma to giant cell tumors of the bone. The studies done by the RCN represent a wide range of rare pathologies that were previously only studied in small series or case reports. With further growth of the RCN and collaboration between members our ability to analyze rare tumors will increase and result in better understanding of their behavior and ultimately help direct research that may improve patient outcomes.

PURPOSE: Chemotherapy (CT) combined with radiation therapy (RT) is the standard treatment for limited disease small-cell lung cancer (LDSCLC). Many questions including RT dose, fractionation, and sequence of RT/CT administration remain controversial. In this paper, we retrospectively assessed the outcome of patients with LDSCLC treated with radiation of at least 50 Gy.METHODS AND MATERIALS: From December 1997 to January 2006, 69 consecutive patients with LDSCLC were treated at our institutions. Treatment consisted of at least 4 cycles of CT, and 3D conformal thoracic RT. The median age was 61 years (range, 37-78 years). Sequential or concomitant CT/RT was given in 47 (68%) and 22 (32%) of the patients, respectively. The median RT dose was 60 Gy. Prophylactic cranial irradiation (PCI) was administered in 47 (68%) patients.RESULTS: With a median follow-up of 36 months (range, 6-107), 16 patients were alive without disease. The median overall survival time was 24 months, with a 3-year survival rate of 29%. The 3-year disease-free survival (DFS) and loco-regional control (LRC) rates were 23% and 60%, respectively. A better DFS was significantly associated with performance status (PS) 0 (p = 0.004), complete response to treatment (p = 0.03), and PCI group (p = 0.03). A trend towards improved overall survival (OS) was observed for patients who underwent PCI (p = 0.07). Patients treated with sequential CT/RT had a better outcome than those treated with concomitant treatment (3-year DFS rate 27% vs. 13%; p = 0.04). However, PCI was delivered more frequently for the sequential group. No significant dose-response relationship was found in terms of LRC. The multivariate analysis showed that complete response to treatment was the only significant factor for OS.CONCLUSION: Complete response to treatment was the most important factor for OS. A better DFS was significantly associated with the PCI group. We did not find a significant difference in outcome between patients receiving doses of 60 Gy or more and patients receiving 60 Gy or less.

To assess the response rate, duration of response, and overall survival after low-dose involved-field radiotherapy in patients with recurrent low-grade lymphoma or chronic lymphocytic leukemia (CLL).Forty-three (24 women, 19 men) consecutive patients with indolent lymphoma or CLL were treated with a total dose of 4 Gy (2 × 2 Gy) using 6- 18-MV photons. The median age was 73 years (range, 39-88). Radiotherapy was given either after (n = 32; 75%) or before (n = 11; 25%) chemotherapy. The median time from diagnosis was 48 months (range, 1-249). The median follow-up period was 20 months (range, 1-56).The overall response rate was 90%. Twelve patients (28%) had a complete response, 15 (35%) had a partial response, 11 (26%) had stable disease, and 5 (11%) had progressive disease. The median overall survival for patients with a positive response (complete response/partial response/stable disease) was 41 months; for patients with progressive disease it was 6 months (p = 0.001). The median time to in-field progression was 21 months (range, 0-24), and the median time to out-field progression was 8 months (range, 0-40). The 3-year in-field control was 92% in patients with complete response (median was not reached). The median time to in-field progression was 9 months (range, 0.5-24) in patients with partial response and 6 months (range, 0.6-6) in those with stable disease (p0.05). Younger age, positive response to radiotherapy, and no previous chemotherapy were the best factors influencing the outcome.Low-dose involved-field radiotherapy is an effective treatment in the management of patients with recurrent low-grade lymphoma or CLL.

AIM: To assess the influence of hemoglobin (Hb) levels in locally advanced head and neck cancer (LAHNC) patients treated with surgery and postoperative radiotherapy (PORT). MATERIAL AND METHODS: Pre- and postoperative Hb levels were collected in 79 patients treated with surgery followed by accelerated PORT for LAHNC. Median follow-up was 52 months (range 12-95 months). RESULTS AND DISCUSSION: Four-year overall survival (OS) rate was 51%. Neither pre- nor postoperative Hb level (

BACKGROUND: The aim of this study was to assess feasibility and efficacy of weekly concomitant boost accelerated postoperative radiation therapy (PORT) with concomitant chemotherapy (CT) in patients with locally advanced head and neck cancer (LAHNC). METHODS AND MATERIALS: Conformal or intensity-modulated 66-Gy RT was performed in 5.5 weeks in 40 patients. Cisplatin was given at days 1, 22, and 43. Median follow-up was 36 months. RESULTS AND DISCUSSION: Grade 3 mucositis, dysphagia, and erythema was observed in ten (25%), nine (23%), and six (13%) patients, respectively. Grade 3 or more anemia was observed in two (6%) patients, and leukopenia in five (13%) patients. No grade 3 or 4 thrombocytopenia was observed. Grade 3 nephrotoxicity was observed in one patient (3%). No treatment-related mortality was observed. Grade 2 or more xerostomia and edema were observed in ten (25%) and one (3%) patient, respectively. Locoregional relapse occurred in eight patients, and seven patients developed distant metastases. Median time to locoregional relapse was 6 months. Three-year overall, disease-free survival, and locoregional control rates were 63%, 62%, and 81%, respectively. Multivariate analysis revealed that the only prognostic factor was nodal status. CONCLUSION: Reducing overall treatment time using accelerated PORT/CT by weekly concomitant boost (six fractions per week) combined with concomitant cisplatin CT is easily feasible with acceptable morbidity.

The management of gliomas in daily clinical practice is challenging. It requires a multidisciplinary and coordinated approach involving neurosurgery, radiotherapy and, finally, chemotherapy. Important progress has been made during the last years with the introduction of a combined treatment associating standard radiotherapy with concomitant chemotherapy using temozolomide, a novel alkylating agent. For the first time in many years a new treatment strategy translated into a significant prolongation of survival. In parallel, molecular markers (e.g. loss of heterozygosity on chromosomes 1p and 19q or methylation of the methyl-guanine methyl transferase [MGMT] gene promoter) allowed for identification of distinct subtypes of glioma or prediction of treatment response. In this "Practical Guide", we describe the daily practice and aim at answering some common questions in the management of patients suffering from glioblastoma, astrocytoma, oligodendroglioma and low grade glioma. The therapeutic options presented here are based on evidences from the literature. In the absence of documented evidence, the empirical choices from our local practice are explained and justified.

Purpose: To investigate whether whole brain irradiation might be replaced by focalized irradiation after resection of a single brain metastasis in patients where extracranial tumor control is deemed to be obtained. Patients and methods: Twelve patients were introduced in a phase I/II prospective study of conformal postoperative external irradiation after resection of a solitary brain metastasis. The radiation treatment consisted of 50.4 Gy (1.8 Gy per fraction, five fractions per week). The planning target volume consisted of the tumor bed and a 2 cm safety margin. All treatments were optimized with head immobilization, dedicated tomodensitometry and computer assisted three-dimensional treatment planning. Results: The median survival was 7.2 months (range 2.4‐50.4 months). Eleven of the 12 patients died. Eight of the 12 patients presented intracranial recurrence and seven died as a consequence of intracranial tumor progression. Conclusions: Focalized external irradiation cannot serve as a reasonable alternative to whole brain radiotherapy (WBRT) even for patients with apparently one single resected brain metastasis. The dogma of ‘one metastasis = multiple metastases’ seems to be confirmed.© 1998 Elsevier Science Ireland Ltd.

Purpose The European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada trial on temozolomide (TMZ) and radiotherapy (RT) in glioblastoma (GBM) has demonstrated that the combination of TMZ and RT conferred a significant and meaningful survival advantage compared with RT alone. We evaluated in this trial whether the recursive partitioning analysis (RPA) retains its overall prognostic value and what the benefit of the combined modality is in each RPA class. Patients and Methods Five hundred seventy-three patients with newly diagnosed GBM were randomly assigned to standard postoperative RT or to the same RT with concomitant TMZ followed by adjuvant TMZ. The primary end point was overall survival. The European Organisation for Research and Treatment of Cancer RPA used accounts for age, WHO performance status, extent of surgery, and the Mini-Mental Status Examination. Results Overall survival was statistically different among RPA classes III, IV, and V, with median survival times of 17, 15, and 10 months, respectively, and 2-year survival rates of 32%, 19%, and 11%, respectively (P < .0001). Survival with combined TMZ/RT was higher in RPA class III, with 21 months median survival time and a 43% 2-year survival rate, versus 15 months and 20% for RT alone (P = .006). In RPA class IV, the survival advantage remained significant, with median survival times of 16 v 13 months, respectively, and 2-year survival rates of 28% v 11%, respectively (P = .0001). In RPA class V, however, the survival advantage of RT/TMZ was of borderline significance (P = .054). Conclusion RPA retains its prognostic significance overall as well as in patients receiving RT with or without TMZ for newly diagnosed GBM, particularly in classes III and IV.

Key words: temozolomide; glioblastoma; clinical trial; neurotherapeutics; radiotherapy; quality of life. Introduction and Overview Glioblastoma multiforme is the most common and devastating of all primary brain tumors, with median survival typically in the range of 9–12 months with multi-modality treatment (DeAngelis, 2001; Burger & Scheithauer, 1994). Even with aggressive therapeutic approaches to prevent and manage tumor progression, and intense efforts to develop better treatments, survival for patients with glioblastoma has changed little in 30 years. Most patients experience local tumor progression, and usually succumb within months of recurrence. Standard accepted initial therapy for this disease has been maximal feasible surgical resection followed by conformal fractionated radiotherapy. Although not generally considered a chemosensitive tumor, glioblastoma occasionally responds to chemotherapeutic agents, particularly when these drugs are administered for recurrent disease (Brada et al ., 2001; Yung et al ., 2000). However, no drugs are predictably active against this disease, and most patients with glioblastoma who receive chemotherapy are usually treated with alkylating agents, historically nitrosoureas and most recently temozolomide (Lesser & Grossman, 1994). Efforts to improve survival for patients with glioblastoma have included advances in surgical techniques that enable more complete tumor resection, and more sophisticated ways of delivering radiotherapy to the tumor bed while comparatively sparing normal brain; these technical advances have made treatment safer, but have not had a definitive impact on extending survival. Chemotherapy has also been evaluated as initial treatment with surgery and radiotherapy in an attempt to improve dismal survival statistics for glioblastoma. The choice of potential agents for evaluation in glioblastoma has been limited by concerns surrounding effective drug penetration into the central nervous system (CNS), which is protected by a blood–brain barrier that renders tumors at least partly impervious to most drugs.

Purpose: The aim of this study was to assess the outcome in patients with penile cancer. Methods and Materials: A total of 60 patients with penile carcinoma were included. Of the patients, 45 ( n = 27) underwent surgery, and 51 underwent definitive ( n = 29) or postoperative ( n = 22) radiotherapy (RT). Median follow-up was 62 months. Results: Median time to locoregional relapse was 14 months. Local failure was observed in 3 of 23 patients (13%) treated with surgery with or without postoperative RT vs. in 19 of 33 patients (56%) given organ-sparing treatment ( p = 0.0008). Of 22 local failures, 16 (73%) were salvaged with surgery. Of the 33 patients treated with definitive RT ( n = 29) and the 4 patients refusing RT after excisional biopsy, local control was obtained with organ preservation in 13 (39%). In the remaining 20, 4 patients with local failure underwent salvage conservatively, resulting in an ultimate penis preservation rate of 17 of 33 (52%) patients treated with definitive RT. The 5-year and 10-year probability of surviving with an intact penis was 43% and 26%, respectively. There was no survival difference between the patients treated with definitive RT and primary surgery (56% vs. 53%; p = 0.16). In multivariate analysis, independent factors influencing survival were N-classification and pathologic grade. Surgery was the only independent predictor for better local control. Conclusion: Based on our study findings, in patients with penile cancer, local control is superior with surgery. However, there is no difference in survival between patients treated with surgery and those treated with definitive RT, with 52% organ preservation.

Objective To assess the feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated radiotherapy (RT). Design Retrospective study. Setting University of Lausanne, Lausanne, Switzerland. Patients Thirty-three consecutive patients (male-female ratio, 4.5; median age, 54 years [age range, 39-76 years]). Interventions Between November 2000 and January 2003, the 33 patients were treated with curative definitive (n = 19) or postoperative (n = 14) RT with (n = 26) or without (n = 7) chemotherapy. All patients received conformal RT. Fractionation schedule consisted of concomitant-boost (Friday afternoon session) accelerated RT using 70 Gy (2 Gy per fraction) in 6 weeks in patients treated with definitive RT and 66 Gy (2 Gy per fraction) in 5 weeks and 3 days in the postoperative setting. Parotid glands received at least 50 Gy in all patients. Amifostine was administered to a total dose of 500 mg subcutaneously, 15 to 30 minutes before morning RT sessions. Results All patients received their planned treatment (including chemotherapy). Ten patients received the full schedule of amifostine (at least 25 injections), 9 received 20 to 24 doses, 4 received 10 to 19 doses, 5 received 5 to 9 doses, and 5 received fewer than 5 doses. Fifteen patients (45%) did not show any intolerance related to amifostine use. Amifostine therapy was discontinued because of nausea in 11 patients (33%) and hypotension in 6 patients (18%), and 1 patient refused treatment. No grade 3, amifostine-related, cutaneous toxic effects were observed. Radiotherapy-induced grade 3 acute toxic effects included mucositis in 14 patients (42%), erythema in 14 patients (42%), and dysphagia in 13 patients (39%). Late toxic effects included grade 2 or more xerostomia in 17 patients (51%) and fibrosis in 3 patients (9%). Grade 2 or more xerostomia was observed in 8 (42%) of 19 patients receiving 20 injections or more vs 9 (64%) of 14 patients receiving fewer than 20 injections ( P = .15). Conclusions Subcutaneous amifostine administration in combination with accelerated concomitant-boost RT with or without chemotherapy is feasible. The major adverse effect of subcutaneous administration was nausea despite prophylactic antiemetic medication, and hypotension was observed in only 6 patients (18%).

Treatment of malignant glioma requires a multidisciplinary team. Treatment includes surgery, radiotherapy, and chemotherapy. Recently developed agents have demonstrated activity against recurrent malignant glioma and efficacy if given concurrently with radiotherapy in the upfront setting. Oligodendroglioma with 1p/19q deletions has been recognized as a distinct pathologic entity with particular sensitivity to radiotherapy and chemotherapy. Randomized trials have shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed in patients whose tumors have a methylated methylguanine methyltransferase gene promoter and are thus unable to repair some of the chemotherapy-induced DNA damage. For lower-grade glioma, the use of chemotherapy remains limited to recurrent disease, and first-line administration is the subject of ongoing clinical trials. Irinotecan and agents like gefitinib, erlotinib, and imatinib targeting the epidermal growth factor receptor and platelet-derived growth factor receptor have shown some promise in recurrent malignant glioma. This review summarizes recent developments, focusing on the clinical management of patients in daily neuro-oncology practice.

Contains fulltext : 50346.pdf (Publisher’s version ) (Closed access) PURPOSE: To retrospectively analyze a series of mucosal melanoma of the upper aerodigestive tract to determine the prognostic factors and contribute to understanding the role of radiotherapy in the therapeutic strategy. METHODS AND MATERIALS: Seventy-four patients were analyzed. The most frequent locations were nasal and oral, in 31 patients (41.9%) and 12 patients (16.2%), respectively. Sixty-three patients (85.1%) were in Stage I, 5 (6.8%) in Stage II, and 6 (8.1%) in Stage III. Treatment consisted of surgery in 17 patients (23.0%), surgery and radiotherapy in 42 (56.8%), radiotherapy in 11 (14.9%), and chemo-immunotherapy in 4 (5.4%). Median follow-up was 20 months. RESULTS: Local control at 3 years was 57% after surgery alone and 71% after surgery and radiotherapy. Overall and disease-free survival rates, respectively, were 41% and 31% at 3 years and 14% and 22% at 10 years. After univariate analysis, female gender, melanosis, tumor size

Purpose To assess the clinical profile, treatment outcome, and prognostic factors in primary spinal epidural lymphoma (PSEL). Methods and Materials Between 1982 and 2002, 52 consecutive patients with PSEL were treated in nine institutions of the Rare Cancer Network. Forty-eight patients had an Ann Arbor stage IE and four had a stage IIE. Forty-eight patients underwent decompressive laminectomy, all received radiotherapy (RT) with ( n = 32) or without chemotherapy ( n = 20). Median RT dose was 36 Gy (range, 6–50 Gy). Results Six (11%) patients progressed locally and 22 (42%) had a systemic relapse. At last follow-up, 28 patients were alive and 24 had died. The 5-year overall survival, disease-free survival, and local control were 69%, 57%, and 88%, respectively. In univariate analyses, favorable prognostic factors were younger age and complete neurologic response. Multivariate analysis showed that combined modality treatment, RT volume, total dose more than 36 Gy, tumor resection, and complete neurologic response were favorable prognostic factors. Conclusions Primary spinal epidural lymphoma has distinct clinical features and outcome, with a relatively good prognosis. After therapy, local control is excellent and systemic relapse occurs in less than half the cases. Combined modality treatment appears to be superior to RT alone.

Two stereotactic surgery methods, arc and micro-multi-leave collimator (MMLC) therapy, were compared in the particular case of arteriovenous malformations (AVMs) treatment. Different methods of the treatment optimisation were used. The comparison covered a group of 22 patients suffering from peripheral and central AVMs of different sizes who underwent initially arc therapy. Several parameters were evaluated to compare the two methods: 2D and 3D isodose representations, dose-volume histograms (DVHs) and probability of success. The 3D isodoses were compared for the 22 patients showing a better conformity for the MMLC (three cases are presented). The DVHs of the AVM were also in favour of MMLC. In terms of probability of success, the results showed that are therapy was superior only in the case of small spherical lesions. MMLC therapy proved to be superior to arc therapy in all cases but central spherical small volume AVMs.

Summary Background A randomised controlled trial of radiotherapy alone versus radiotherapy with concomitant and adjuvant temozolomide for patients with glioblastoma showed that survival was higher for patients assigned combination treatment compared with those assigned standard radiotherapy alone. This paper reports the health-related quality of life (HRQOL) of the patients in this trial. Methods 573 patients with newly diagnosed glioblastoma were randomly allocated either radiotherapy alone or radiotherapy and temozolomide. The primary endpoint was survival, and HRQOL was a secondary endpoint. We assessed HRQOL at baseline and at every 3 months during treatment until progression using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) and the EORTC brain cancer module (EORTC BN-20). We calculated changes from baseline score for seven predefined HRQOL measures (fatigue, overall health, social function, emotional function, future uncertainty, insomnia, and communication deficit) and differences between groups for these measures at every time point. The significance of, and proportions of patients with, improved HRQOL scores—defined as a change of 10 points or more—were recorded. This trial is registered on the US National Cancer Institute website http://www.cancer.gov/search/NewClinicalTrials, NCT00006353. Findings Baseline questionnaires were available for 490 (86%) patients. Baseline HRQOL scores did not differ between groups. At first follow-up, groups differed only in social functioning, favouring the radiotherapy-only group (mean score 79·0 [SD 3·2] for patients assigned radiotherapy vs 67·4 [2·7] for those assigned radiotherapy and temozolomide; difference between groups 11·6 points [95% CI 3·5–19·7], p=0·0052). Over subsequent assessments, HRQOL was much the same between treatment groups. Interpretation Addition of temozolomide during and after radiotherapy for patients with newly diagnosed glioblastoma significantly improved survival without a negative effect on HRQOL.

Heterotopic ossification, mostly of the hip, is a frequent complication after reconstructive surgery. Most common prophylactic therapies are non-steroidal anti-inflammatory medication (AINS) applied post-operatively and external radiotherapy (RT) administered in the pre- or post-operative setting. Both treatments proved to be efficient in several randomised clinical trials. Prevailing trend regarding RT is a treatment prior to surgery. It is appreciated by both physician and the patient because it is simple and comfortable. In this article, we present the literature linked to the subject together with the benefit and the inconvenience of both therapeutic methods.

Meningiomas account for about 20% of intracranial and 25% of intraspinal tumours. They are generally well circumscribed and slow-growing but there are wide variations in their natural evolution, from small, indolent and asymptomatic tumours to lesions encasing major vessels, cranial nerves, optic pathways or compressing vital structures of the brain, thus causing major morbidity and even mortality. Between 90 and 95% of meningiomas are benign, 5% are called atypical and 2 – 3% are clearly malignant. The latter two categories undisputedly deserve an aggressive, combined therapeutic approach with surgery

The phase III randomised European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trail Group (NCIC) Intergroup trial (EORTC 26981/22981; CE3) compares irradiation alone with irradiation plus temozolomide for patients with glioblastoma multiforme (GBM). We evaluated the compliance to radiotherapy (RT) guidelines. All 8 5 recruiting centres were invited to participate in the individual case review. Fifty-four centres (64%) entering 71% of the patients provided data on one randomly selected patient. All participating centres used individual head immobilisation and computerised tomography (CT)-based treatment planning. Most (74%) performed three-dimensional conformal radiotherapy (3-D-CRT) including dose-volume histograms. Ninety-four percent performed portal imaging at least once. Planning target volume (PTV) and structures at risk were delineated in most of the centres (94%). Although the PTV received

Low-grade gliomas are a heterogenous group of diseases characterized by relatively slow-growing primary brain tumors of astrocytic and/or oligodendroglial origin. Many patients present with easily controlled seizures and remain stable for years, whereas others progress rapidly to higher-grade tumors. Several studies have retrospectively investigated tumor-, patient-, and treatment-related prognostic factors in this patient population. Tumor histology, grade, location, contrast enhancement, and molecular markers have been identified as prognostic factors for survival. Likewise, patient age, performance status, and seizure history are patient-dependent prognostic factors. However, although patients who undergo surgical resection and receive adjuvant radiotherapy tend to have improved survival, treatment-dependent prognostic factors have yet to be definitively identified. Recursive partitioning and multivariant analyses have identified a class of patients with good prognosis. Younger patients with good performance status, non-contrast-enhancing tumors (

PURPOSE: To assess the outcome and patterns of failure in patients with testicular lymphoma treated by chemotherapy (CT) and/or radiation therapy (RT). METHODS AND MATERIALS: Data from a series of 36 adult patients with Ann Arbor Stage I (n = 21), II (n = 9), III (n = 3), or IV (n = 3) primary testicular lymphoma, consecutively treated between 1980 and 1999, were collected in a retrospective multicenter study by the Rare Cancer Network. Median age was 64 years (range: 21-91 years). Full staging workup (chest X-ray, testicular ultrasound, abdominal ultrasound, and/or thoracoabdominal computer tomography, bone marrow assessment, full blood count, lactate dehydrogenase, and cerebrospinal fluid evaluation) was completed in 18 (50%) patients. All but one patient underwent orchidectomy, and spermatic cord infiltration was found in 9 patients. Most patients (n = 29) had CT, consisting in most cases of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with (n = 17) or without intrathecal CT. External RT was delivered to scrotum alone (n = 12) or testicular, iliac, and para-aortic regions (n = 8). The median RT dose was 31 Gy (range: 20-44 Gy) in a median of 17 fractions (10-24), using a median of 1.8 Gy (range: 1.5-2.5 Gy) per fraction. The median follow-up period was 42 months (range: 6-138 months). RESULTS: After a median period of 11 months (range: 1-76 months), 14 patients presented lymphoma progression, mostly in the central nervous system (CNS) (n = 8). Among the 17 patients who received intrathecal CT, 4 had a CNS relapse (p = NS). No testicular, iliac, or para-aortic relapse was observed in patients receiving RT to these regions. The 5-year overall, lymphoma-specific, and disease-free survival was 47%, 66%, and 43%, respectively. In univariate analyses, statistically significant factors favorably influencing the outcome were early-stage and combined modality treatment. Neither RT technique nor total dose influenced the outcome. Multivariate analysis revealed that the most favorable independent factors predicting the outcome were younger age, early-stage disease, and combined modality treatment. CONCLUSIONS: In this multicenter retrospective study, CNS was found to be the principal site of relapse, and no extra-CNS lymphoma progression was observed in the irradiated volumes. More effective CNS prophylaxis, including combined modalities, should be prospectively explored in this uncommon site of extranodal lymphoma.

Purpose : A comparative treatment planning study has been undertaken between standard photon delivery techniques,b intensity modulated photon methods and spot scanned protons in order to investigate the merits and limitations of each of these treatment approaches. Methods : Plans for each modality were performed using CT scans and planning information for nine patients with varying indications and lesion sites and the results have been analysed using a variety of dose and volume based parameters. Results : Over all cases, it is predicted that the use of protons could lead to a reduction of the total integral dose by a factor three compared to standard photon techniques and a factor two compared to IM photon plans. In addition, in all but one Organ at Risk (OAR) for one case, protons are predicted to reduce both mean OAR dose and the irradiated volume at the 50% mean target dose level compared to both photon methods. However, when considering the volume of an OAR irradiated to 70% or more of the target dose, little difference could be shown between proton and intensity modulated photon plans. On comparing the magnitude of dose hot spots in OARs resulting from the proton and IM photon plans, more variation was observed, and the ranking of the plans was then found to be case and OAR dependent. Conclusions : The use of protons has been found to reduce the medium to low dose load (below about 70% of the target dose) to OARs and all non-target tissues compared to both standard and inversely planned photons, but that the use of intensity modulated photons can result in similar levels of high dose conformation to that afforded by protons. However, the introduction of inverse planning methods for protons is necessary before general conclusions on the relative efficacy of photons and protons can be drawn.

Purpose : This retrospective study was undertaken to clarify the role of high energy external beam radiation therapy (EBRT) and to determine its safety and efficacy on local control and visual acuity in patients suffering from choroidal metastases (CM). Materials and methods : The records of 58 consecutive patients treated with EBRT between 1970 and 1993 were analyzed. The female to male ratio was 2.9 and the median age was 59 years (range 40–81 years). Thirty-six patients (62%) had unilateral CM and 22 patients had bilateral CM. The mean number of lesions per eye was two. Retinal detachment was present in 65% of cases. The primary tumour (PT) was breast carcinoma for 38 patients (75%), lung carcinoma for 10 patients (17%) and gastrointestinal, genitourinary or unknown PT for the remaining 10 patients. The median interval of time between the PT and the CM was 55 months (range 0–228 months). All patients were treated with megavoltage irradiation. The median prescribed dose was 35.5 Gy (range 20–53 Gy) normalized at a 2 Gy per fraction schedule with an α / β value of 10 Gy. Various techniques were used and whenever possible the lens was spared. Ten patients with unilateral disease were treated in both eyes. Results : The tumour response was slow. When assessed after 3 months or more, the complete response rate was 53% with significantly better results for doses higher than 35.5 Gy (72 versus 33%; P =0.009). Visual acuity was improved or stabilized in 62% of patients, with also significantly better results when doses higher than 35.5 Gy ( P =0.014) were administered. Amongst 26 patients with unilateral CM who had no elective contralateral irradiation, three developed metastasis in the opposite eye versus none of the 10 patients who had bilateral irradiation. Five complications occurred (three cataracts, one retinopathy and one glaucoma). Conclusion : Radiation therapy is an efficient and safe palliative treatment for choroidal metastases and it helps the preservation of vision. Thus, there is a major impact on the quality of life in a group of patients with an almost uniformly fatal prognosis. Both tumour response and visual acuity are significantly improved if doses higher than 35.5 Gy are administered. Whenever possible, a lens sparing technique should be used.