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ABSTRACT: PURPOSE: To investigate the prognostic value of epidermal growth factor receptor (EGFR) expression in pretreatment tumor biopsy specimens of patients with anal cancer treated with concurrent 5-fluorouracil and mitomycin C-based chemoradiation therapy (CRT). METHODS AND MATERIALS: Immunohistochemical staining for EGFR was performed in pretreatment biopsy specimens of 103 patients with anal carcinoma. EGFR expression was correlated with clinical and histopathologic characteristics and with clinical endpoints, including local failure-free survival (LFFS), colostomy-free survival (CFS), distant metastases-free survival (DMFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: EGFR staining intensity was absent in 3%, weak in 23%, intermediate in 36% and intense in 38% of the patients. In univariate analysis, the level of EGFR staining was significantly correlated with CSS (absent/weak vs intermediate/intense expression: 5-year CSS, 70% vs 86%, P=.03). As a trend, this was also observed for DMFS (70% vs 86%, P=.06) and LFFS (70% vs 87%, P=.16). In multivariate analysis, N stage, tumor differentiation, and patients' sex were independent prognostic factors for CSS, whereas EGFR expression only reached borderline significance (hazard ratio 2.75; P=.08). CONCLUSION: Our results suggest that elevated levels of pretreatment EGFR expression could be correlated with favorable clinical outcome in anal cancer patients treated with CRT. Further studies are warranted to elucidate how EGFR is involved in the response to CRT.
International journal of radiation oncology, biology, physics 06/2013; · 4.59 Impact Factor
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ABSTRACT: BACKGROUND: To examine whether nuclear NF-κB expression correlates with outcome in patients with head and neck squamous cell carcinoma (HNSCC) treated with primary chemoradiation therapy (CRT). METHODS AND MATERIALS: Between 2007 and 2010, 101 patients with locally advanced primary HNSCC were treated with definitive simultaneous CRT. Pretreatment biopsy specimens were analyzed for NF-κB p65 (RelA) nuclear immunoreactivity. A sample was assigned to be positive with more than 5% positive nuclear expression. The predictive relevance of NF-κB and clinicopathologic factors for overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS), and metastasis-free survival (DMFS) was examined by univariate and multivariate analysis. RESULTS: No significant differences between the groups were observed with regard to age, sex, total radiation dose, fractionation mode, total chemotherapy applied, T stage or grading. Patients with p65 nuclear positive biopsy specimens showed significantly a higher rate of lymph node metastasis (cN2c or cN3 status, P=.034). Within a mean follow-up time of 25 months (range, 2.33-62.96 months) OS, PFS, and DMFS were significantly poorer in the p65 nuclear positive group (P=.008, P=.027, and P=.008, respectively). These correlations remained significant in multivariate analysis. CONCLUSION: NF-κB/p65 nuclear expression is associated with increased lymphatic and hematogenous tumor dissemination and decreased survival in HNSCC patients treated with primary CRT. Our results may foster further investigation of a predictive relevance of NF-κB/p65 and its role as a suitable target for a molecular-based targeted therapy in HNSCC cancer.
International journal of radiation oncology, biology, physics 05/2013; · 4.59 Impact Factor
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ABSTRACT: INTRODUCTION: Renal cell carcinoma is counted among the most resistant tumors to chemotherapy and radiotherapy, respectively. However, therapeutic options expanded since the introduction of molecular agents, targeting specific pathways such as the vascular endothelial growth factor (VEGF)-α, the VEGF receptor (VEGFR), or the mammalian target of rapamycin (mTOR) pathway. These new agents almost doubled the time to tumor progression and in some trials even improved overall survival. Against this background, the role of local treatment strategies in metastasized or inoperable primary renal cell carcinoma has to be redefined. With the onset of new technical developments in radiotherapy and the possibility to precisely deliver higher doses per fraction, encouraging response and control rates have been reported for kidney cancer, supporting a possible role for irradiation in this setting. This overview summarizes the preclinical data and clinical experiences of modern radiotherapy with focus on possible synergies and toxicities when combined with molecular targeted agents. METHODS: The available literature on preclinical and clinical data comprising prospective trials, retrospective analyses and case reports was reviewed. CONCLUSION: With the recent developments in stereotactic and image-guided radiotherapy, encouraging data concerning local control in the treatment for metastasized renal cell carcinoma have been generated and are therefore recommended whenever possible. It seems that with these high- precision irradiation schedules, the combination with targeted agents is feasible with no increase in severe adverse events. Nevertheless, the addition of molecular targeted drugs to radiotherapy outside of approved regimens or clinical trials warrants careful consideration for every single case.
World Journal of Urology 05/2013; · 2.41 Impact Factor
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ABSTRACT: BACKGROUND: Preoperative radiochemotherapy (RCT) with 5-FU or capecitabine is the standard of care for patients with locally advanced rectal cancer (LARC). Preoperative RCT achieves pathological complete response rates (pCR) of 10-15%. We conducted a single arm phase II study to investigate the feasibility and efficacy of addition of bevacizumab and oxaliplatin to preoperative standard RCT with capecitabine. METHODS: Eligible patients had LARC (cT3-4; N0/1/2, M0/1) and were treated with preoperative RCT prior to planned surgery. Patients received conventionally fractionated radiotherapy (50.4 Gy in 1.8 Gy fractions) and simultaneous chemotherapy with capecitabine 825 mg/m2 bid (d1-14, d22-35) and oxaliplatin 50 mg/m2 (d1, d8, d22, d29). Bevacizumab 5 mg/kg was added on days 1, 15, and 29. The primary study objective was the pCR rate. RESULTS: 70 patients with LARC (cT3-4; N0/1, M0/1), ECOG < 2, were enrolled at 6 sites from 07/2008 through 02/2010 (median age 61 years [range 39--89], 68% male). At initial diagnosis, 84% of patients had clinical stage T3, 62% of patients had nodal involvement and 83% of patients were M0. Mean tumor distance from anal verge was 5.92 cm (+/- 3.68). 58 patients received the complete RCT (full dose RT and full dose of all chemotherapy). During preoperative treatment, grade 3 or 4 toxicities were experienced by 6 and 2 patients, respectively: grade 4 diarrhea and nausea in one patient (1.4%), respectively, grade 3 diarrhea in 2 patients (3%), grade 3 obstipation, anal abscess, anaphylactic reaction, leucopenia and neutropenia in one patient (1.4%), respectively. In total, 30 patients (46%) developed postoperative complications of any grade including one gastrointestinal perforation in one patient (2%), wound-healing problems in 7 patients (11%) and bleedings in 2 patients (3%). pCR was observed in 12/69 (17.4%) patients. Pathological downstaging (ypT < cT and ypN <= cN) was achieved in 31 of 69 patients (44.9%). All of the 66 operated patients had a R0 resection. 47 patients (68.1%) underwent sphincter preserving surgery. CONCLUSIONS: The addition of bevacizumab and oxaliplatin to RCT with capecitabine was well tolerated and did not increase perioperative morbidity or mortality. However, the pCR rate was not improved in comparison to other trials that used capecitabine or capecitabine/oxaliplatin in preoperative radiochemotherapy.
Radiation Oncology 04/2013; 8(1):90. · 2.32 Impact Factor
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Markus Moehler,
Ines Gockel,
Hans-Peter Roessler,
Dirk Arnold,
Tanja Trarbach,
Thomas Thomaidis,
Gunther Klautke, Claus Rödel,
Baruch Brenner,
Hauke Lang,
Peter R Galle,
Carl C Schimanski,
Heinz Schmidberger
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ABSTRACT: BACKGROUND: This phase I/II-trial assessed the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of neoadjuvant radiochemotherapy (RCT) with docetaxel and oxaliplatin in patients with locally advanced adenocarcinoma of the oesophagogastric junction. METHODS: Patients received neoadjuvant radiotherapy (50.4 Gy) together with weekly docetaxel (20 mg/m2 at dose level (DL) 1 and 2, 25 mg/m2 at DL 3) and oxaliplatin (40 mg/m2 at DL 1, 50 mg/m2 at DL 2 and 3) over 5 weeks. The primary endpoint was the DLT and the MTD of the RCT regimen. Secondary endpoints included overall response rate (ORR) and progression-free survival (PFS). RESULTS: A total of 24 patients were included. Four patients were treated at DL 1, 13 patients at DL 2 and 7 patients at DL 3. The MTD of the RCT was considered DL 2 with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2. Objective response (CR/PR) was observed in 32% (7/22) of patients. Eighteen patients (75%) underwent surgery after RCT. The median PFS for all patients (n = 24) was 6.5 months. The median overall survival for all patients (n = 24) was 16.3 months. Patients treated at DL 2 had a median overall survival of 29.5 months. CONCLUSION: Neoadjuvant RCT with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2 was effective and showed a good toxicity profile. Future studies should consider the addition of targeted therapies to current neoadjuvant therapy regimens to further improve the outcome of patients with advanced cancer of the oesophagogastric junction.Registered trial at clinical trials.gov: NCT00374985.
BMC Cancer 02/2013; 13(1):75. · 3.01 Impact Factor
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Lena-Christin Conradi,
Hanna Styczen,
Thilo Sprenger,
Hendrik A Wolff, Claus Rödel,
Manuel Nietert,
Kia Homayounfar,
Jochen Gaedcke,
Julia Kitz,
Recca Talaulicar,
Heinz Becker,
Michael Ghadimi,
Peter Middel,
Tim Beissbarth,
Josef Rüschoff,
Torsten Liersch
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ABSTRACT: In patients with advanced rectal cancer (cUICC II and III) multimodality therapy resulted in better long-term local tumor control. Ongoing clinical trials are focusing on therapy intensification to improve disease-free (DFS) and cancer-specific survival (CSS), the integration of biomarkers for prediction of individual recurrence risk, and the identification of new targets. In this context, we investigated HER-2, a member of the epidermal growth factor receptor family, whose expression pattern and role was unclear in rectal cancer. A total of 264 patients (192 male, 72 female; median age 64 y) received standardized multidisciplinary treatment according to protocols of phase II/III trials of the German Rectal Cancer Study Group. HER-2 status was determined in pretherapeutic biopsies and resection specimens using immunohistochemistry scoring and detection of silver in situ hybridization amplification. Tumors with an immunohistochemistry score of 3 or silver in situ hybridization ratios of ≥2.0 were classified HER-2 positive; these results were correlated with clinicopathologic parameters [eg, resection (R) status, nodal status ((y)pN)], DFS, and CSS. Positive HER-2 status was found in 12.4% of biopsies and in 26.7% of resected specimens. With a median follow-up of 46.5 months, patients with HER-2 positivity showed in trend a better DFS (P=0.1) and a benefit in CSS (P=0.03). The 5-year survival rate was 96.0% (HER-2 positive) versus 80.0% (HER-2 negative). In univariate and multivariate analyses, HER-2 was an independent predictor for CSS (0.02) along with the (y)pN status (P<0.00001) and R status (P=0.011). HER-2 amplification is detectable in a relevant proportion (26.7%) of rectal cancer patients. For the development of innovative new therapies, HER-2 may represent a promising target and should be further assessed within prospective clinical trials.
The American journal of surgical pathology 12/2012; · 4.06 Impact Factor
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ABSTRACT: Brain metastases (BM) occur in 20% to 40% of patients with cancer and result in significant morbidity and poor survival. The main therapeutic options include surgery, whole brain radiotherapy, stereotactic radiosurgery and chemotherapy. Although significant progress has been made in diagnostic and therapeutic methods, the prognosis in these patients remains poor. Furthermore, the poor penetrability of chemotherapy agents through the blood brain barrier (BBB) continues to pose a challenge in the management of this disease. Preclinical evidence suggests that new targeted treatments can improve local tumor control but our clinical experience with these agents remains limited. In addition, several clinical studies with these novel agents have produced disappointing results. This review will examine the knowledge of targeted therapies in BM. The preclinical and clinical evidence of their use in BM induced by breast cancer, non-small cell lung cancer and melanoma will be presented. In addition, we will discuss the role of antiangiogenic and radiosensitising agents in the treatment of BM and the current strategies available to increase BBB permeability. A better understanding of the mechanism of action of these agents will help us to identify the best targets for testing in future clinical studies.
Biochimica et Biophysica Acta 11/2012; · 4.66 Impact Factor
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ABSTRACT: PURPOSE: To evaluate sex as a possible prognostic factor in bladder cancer patients treated with transurethral resection (TURBT) and radio- (RT) or radiochemotherapy (RCT). METHODS: Kaplan-Meier analyses and multiple Cox proportional hazards regression analyses were performed to analyze sex as a possible prognostic factor on the overall (OS) and cancer-specific (CSS) survival of 386 male and 105 female patients who underwent TURBT and RCT or RT with curative intent between 1982 and 2007. RESULTS: After a follow-up of 5 years, female sex demonstrated a hazard ratio (HR) of 1.79 (95 % CI 1.24-2.57) for OS; for CSS, the HR was 2.4 (95 % CI 1.52-3.80). Sex was an adverse prognosticator of both OS and CSS independent from age at diagnosis, cT stage, grading, concurrent cis, LVI, focality, therapy response, resection status and therapy mode. Kaplan-Meier analysis showed significantly reduced OS of women compared with men, with a median survival of 2.3 years for female patients and 5.1 years for male patients (p = 0.045, log-rank test). The estimated median CSS was 7.1 years for female patients and 12.7 years for male patients (p = 0.11, log-rank test). CONCLUSIONS: Female sex is an independent prognostic factor for reduced OS and CSS in bladder cancer patients treated by TURBT and RT or RCT. These data are in agreement with those reported for OS after radical cystectomy in muscle-invasive bladder cancers. Therefore, further studies are strongly warranted to obtain more information about molecular differences regarding sex-specific carcinogenesis in bladder cancer and about possible therapeutic considerations.
World Journal of Urology 10/2012; · 2.41 Impact Factor
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ABSTRACT: The 2 broad approaches to preoperative therapy for rectal cancer are chemoradiation and short-course radiation. The outcomes of these 2 approaches reported in nonrandomized trials are not comparable because patients selected for treatment with short-course radiotherapy included those with cT1-3 disease, whereas patients selected for chemoradiation included those with T3 and/or N+ disease. However, more recent trials of short-course radiation have included patients with cT3 and/or N+ disease who also underwent sequential or postoperative chemotherapy, allowing a more relevant comparison with chemoradiation. This article compares the 2 preoperative approaches and addresses their emerging roles.
Journal of the National Comprehensive Cancer Network: JNCCN 10/2012; 10(10):1223-31. · 4.41 Impact Factor
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Thilo Sprenger,
Lena-Christin Conradi,
Tim Beissbarth,
Heiko Ermert,
Kia Homayounfar,
Peter Middel,
Josef Rüschoff,
Hendrik A Wolff,
Philipp Schüler,
B Michael Ghadimi, Claus Rödel,
Heinz Becker,
Franz Rödel,
Torsten Liersch
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ABSTRACT: BACKGROUND: The transmembrane glycoprotein CD133 (cluster of differentiation 133; also known as Prominin or PROM1) has been described as a potential stem cell marker in colorectal cancer and is associated with higher tumorigenic potential and resistance to radiochemotherapy (RCT). In this study, CD133 expression was evaluated in pre-RCT tumor biopsies and the corresponding post-RCT surgical specimens from patients with locally advanced rectal adenocarcinoma, and expression levels were correlated with histopathologic features and clinical follow-up. METHODS: One hundred twenty-six patients with International Union Against Cancer (UICC) stage II/III rectal cancer who received preoperative 5-fluorouracil (5-FU)-based RCT within the German Rectal Cancer Trials were investigated. Pre-RCT and post-RCT CD133 expression levels were determined using immunohistochemistry and were correlated with histopathologic parameters, tumor regression grade, cancer recurrence, and patient survival. RESULTS: Compared with pre-RCT biopsies, significantly higher CD133 expression was observed in tumor specimens (P = .01). However, no correlations were observed for either biopsies or tumor specimens between CD133 expression levels, histopathologic characteristics, or survival. In matched analyses of corresponding biopsy/tumor pairs, patients who had an increased fraction of CD133-expressing (CD133+) cells after preoperative RCT had significantly higher residual tumor stages (P = .02) and lower histopathologic tumor regression (P < .01). Moreover, these patients had significantly reduced disease-free survival and cancer-specific overall survival in univariate analysis (P < .001 and P = .004, respectively) and multivariate analysis (P = .003 and P = .024, respectively). CONCLUSIONS: The enrichment of CD133+ cancer cells during preoperative RCT was correlated with minor local tumor response, increased distant cancer recurrence, and decreased survival. The current results indicate that the up-regulation of intratumoral CD133 expression, in contrast to absolute pre-RCT and post-RCT CD133 levels, plays an important role in tumor progression and metastasis in patients with rectal cancer who are receiving neoadjuvant RCT. Cancer 2012. © 2012 American Cancer Society.
Cancer 06/2012; · 4.77 Impact Factor
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ABSTRACT: One of the main challenges in radiation oncology is to overcome the resistance of cancer cells against treatment by molecular targeted approaches. Among the most promising targets is the inhibitor of apoptosis protein survivin, known to be associated with increased tumour aggressiveness and therapy resistance. The objective of this study was the development of a human serum albumin-based nanoparticulate carrier system for plasmid-mediated RNA interference (miRNA) and the investigation of its in vitro efficacy on survivin knockdown and cellular toxicity in SW480 colorectal cancer cells. The results demonstrate a robust nanoparticulate system of a size around 220 nm with a plasmid incorporation efficacy of about 90%. Moreover, treatment of carcinoma cells with survivin-miRNA nanoparticles resulted in reduction of survivin expression by 50% and increased cytotoxicity if combined with ionising irradiation. These nanoparticles comprise a promising option to enhance the response of carcinoma cells to therapy with ionising irradiation.
Journal of Microencapsulation 06/2012; · 1.55 Impact Factor
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ABSTRACT: To investigate the prognostic value of survivin expression in pretreatment specimens from patients with anal cancer treated with concurrent 5-FU and mitomycin C-based chemoradiation (CRT).
Immunohistochemical staining for survivin was performed in pretreatment biopsies of 62 patients with anal carcinoma. Survivin expression was correlated with clinical and histopathological characteristics as well as local failure free- (LFFS), distant metastases free- (DMFS), cancer specific- (CSS), and overall survival (OS).
Survivin staining intensity was weak in 10%, intermediate in 48% and intense in 42% of the patients. No association between survivin expression and clinicopathologic factors (tumor stage, age and HIV status) could be shown. In univariate analysis, the level of survivin staining was significantly correlated with DMFS (low survivin vs. high survivin: 94% vs. 74%, p = 0.04). T-stage, N-stage and the tumor grading were significantly associated with OS and CSS and with DMFS and LFFS, respectively. In multivariate analysis, survivin was confirmed as independent prognostic parameter for DMFS (RR, 0.04; p = 0.02) and for OS (RR, 0.27; p = 0.04).
Our results demonstrated that the level of pretreatment survivin is correlated with the clinical outcome in patients with anal carcinoma treated with concurrent CRT. Further studies are warranted to elucidate the complex role of survivin for the oncologic treatment and to exploit the protein as a therapeutic target in combined modality treatment of anal cancer.
Radiation Oncology 06/2012; 7:88. · 2.32 Impact Factor
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Nature Reviews Clinical Oncology 05/2012; 9(7):374-5. · 11.96 Impact Factor
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Claus Rödel,
Torsten Liersch,
Heinz Becker,
Rainer Fietkau,
Werner Hohenberger,
Torsten Hothorn,
Ullrich Graeven,
Dirk Arnold,
Marga Lang-Welzenbach,
Hans-Rudolf Raab, [......],
Sergej Potapov,
Ludger Staib,
Clemens Hess,
Karin Weigang-Köhler,
Gerhard G Grabenbauer,
Hans Hoffmanns,
Fritz Lindemann,
Anke Schlenska-Lange,
Gunnar Folprecht,
Rolf Sauer
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ABSTRACT: Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment.
This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m(2) days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m(2) days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m(2) days 1 and 15), leucovorin (400 mg/m(2) days 1 and 15), and infusional fluorouracil (2400 mg/m(2) days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076.
Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group.
Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS.
German Cancer Aid (Deutsche Krebshilfe).
The lancet oncology 05/2012; 13(7):679-87. · 14.47 Impact Factor
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ABSTRACT: Novel strategies to overcome an irradiation resistant phenotype may help to increase therapeutic efficacy in glioblastoma multiforme. The present study aimed to elucidate radiation sensitizing properties of artesunate, a semi synthetic derivate of artemisinin and to assess factors involved in this effect.
LN229 and U87MG cells were treated with various concentrations of artesunate and radiation response was determined by a colony forming assay. Cell numbers, apoptosis induction, cell cycle distribution, and DNA repair following combined modality treatment were monitored by MTT-, caspase 3/7 assay, cytofluorometry, and γ-H2AX foci formation. Expression of survivin, survivin-GFP fusion protein, XIAP, cellular (c)IAP1 and cIAP2 was monitored by Western immunoblotting.
Treatment of glioma cells with artesunate and irradiation resulted in an increased apoptotic fraction, pronounced G2/M arrest and increased DNA damage as demonstrated by an elevated amount of γ-H2AX foci/nucleus. Incubation with artesunate lowers survivin expression in a time and dose-dependent manner, whereas expression of XIAP, cIAP1 and cIAP2 was not affected. In clonogenic assays, treatment with artesunate revealed a significantly reduced surviving fraction, whereas stable over expression of a survivin-GFP protein reversed artesunate-mediated radiosensitization.
Artesunate selectively down regulates survivin that contributes to a radio-sensitization of glioma cells by an increased induction of apoptosis, cell cycle arrest, and a hampered DNA damage response.
Radiotherapy and Oncology 05/2012; 103(3):394-401. · 5.58 Impact Factor
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ABSTRACT: BackgroundThe objective of this retrospective analysis was to assess long-term outcome and prognostic factors of unselected patients
treated for glioblastoma (GB) at a single center with surgery, standard radiotherapy (RT), and concomitant temozolomide (TMZ).
From 1999–2005, the institutional protocol included surgery and RT with TMZ. From 2005 on, adjuvant TMZ was routinely added.
Patients and MethodsBetween April 1999 and September 2009, 181 patients with GB were treated with RT (60 Gy in 30 fractions) and concomitant TMZ
(75 mg/m2/day throughout RT). Biopsy only had been performed in 53 patients (29.3%), 128 patients (70.7%) had undergone resection,
which was complete based on postoperative MRI in 51 patients (28.2%). Adjuvant TMZ was applied in 67 of 181 patients (37%).
ResultsMedian overall survival (OS) and progression-free survival (PFS) were 15.0 (95% CI, 13.1–16.8) and 7.2 months (95% CI, 5.9–8.5),
respectively. After complete resection, partial/subtotal resection and biopsy, median OS was 23.20, 14.75, and 7.89 months
(p < 0.001), respectively. In multivariate Cox proportional hazards regression models, extent of resection (p < 0.0001), Karnofsky’s
performance score (p < 0.0001) and adjuvant TMZ (p = 0.001) were significant independent prognostic factors for OS. RT with
concomitant TMZ was well tolerated in the majority of patients and could be completed as scheduled in 146 patients (80.7%),
while 11 patients (6.1%) discontinued RT. Another 35 patients (19.3%) interrupted concomitant chemotherapy.
ConclusionRT with concomitant TMZ is a feasible regimen with acceptable toxicity in routine practice. Our data are compatible with a
beneficial effect of adjuvant TMZ on OS and PFS.
HintergrundZiel dieser retrospektiven Analyse einer monoinstitutionellen Serie war es, Langzeitergebnisse sowie Prognosefaktoren nach
Operation und simultaner Radiochemotherapie (RCT) mit Temozolomid (TMZ) zu untersuchen. Zwischen 1999 und 2005 erfolgte nach
Operation eine RCT mit TMZ; seit 2005 wurde routinemäßig eine adjuvante TMZ-Chemotherapie hinzugefügt.
Patienten und MethodenVon 04/1999 bis 9/2009, wurden 181 GB-Patienten mit einer kombinierten RCT (60 Gy in 30 Fraktionen) mit TMZ 75 mg/m2/Tag während der RT behandelt. Eine alleinige Biopsie lag bei 53 Patienten (29,3 %) vor. 128 Patienten (70,7 %) wurden reseziert;
davon erreichten 51 Patienten (28,2 %) nach Maßgaben eines postoperativen MRT eine komplette Resektion. Eine adjuvante TMZ-Therapie
erhielten 67 der 181 Patienten (37 %).
ErgebnisseDas mediane Gesamtüberleben (GÜ) und das progressionsfreie Überleben (PFÜ) lag bei 15,0 (95 %-CI: 13,1–16,8 Monate) bzw. 7,2
Monaten (95 %-CI: 5,9–8,5 Monate). Nach kompletter Resektion, partieller/subtotaler Resektion bzw. Biopsie betrug das mediane
GÜ 23,2 bzw. 14,75 und 7,89 Monate (p < 0,001). In der multivariaten Analyse waren Resektionsstatus (p < 0,0001), Karnofsky-Index
(p < 0,0001) und adjuvante TMZ-Therapie (p = 0,001) unabhängige prognostische Faktoren. Von der Mehrzahl der Patienten wurde
die kombinierte RCT gut vertragen und konnte bei 146 Patienten (80,7 %) vollständig durchgeführt werden. Bei 11 Patienten
(6,1 %) wurde die RT abgebrochen. Bei weiteren 35 Patienten wurde die konkomitante Chemotherapie unterbrochen.
SchlussfolgerungDie kombinierte RCT mit TMZ ist in der klinischen Routine ein gut verträgliches Therapieregime mit einer akzeptablen Toxizität.
Die adjuvante Chemotherapie mit TMZ war mit einer Verbesserung des GÜ und PFÜ assoziiert.
Key WordsGlioblastoma multiforme–radiochemotherapy–temozolomide
SchlüsselwörterGlioblastoma multiforme–Radiochemotherapie–Temozolomid
Strahlentherapie und Onkologie 04/2012; 187(11):722-728. · 3.56 Impact Factor
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ABSTRACT: Background:
An electronic portal imaging device (EPID) is used to control for patient setup and positioning during fractionated radiotherapy.
Due to the rising complexity and conformity of irradiation techniques, the demand for an accurate verification of the dose
delivered to the patient has also increased. The purpose of this study was to investigate a simple guidance for dosimetry
with an Elekta iViewGTTM EPID using commercial software modules.
Material and Methods:
EPID measurements were performed using an Elekta iViewGTTM EPID on a linear accelerator with 6 MV x-ray beam. The EPID signal was studied for reproducibility, as well as characteristics
as a function of dose, dose rate, and field size. A series of experiments, comparing the response of the flat panel imager
and ionization chamber measurements of dose, determine the parameters for the calibration model. EPID measurements were also
compared with calculations of the treatment planning system.
Results:
We found a stable response of the EPID signal over a period of 14 months. It showed nonlinearity depending on dose up to 6.8%.
There were low oscillations up to 1.2% depending on dose rate. For all fields, the calibrated flat panel profiles match the
measured and calculated dose profiles with maximum deviation of 2–3% for the in-field region. In the high gradient areas,
higher differences up to 6% were found.
Conclusions:
The gamma evaluation indicates good correlation between predicted and acquired EPID images. The EPID-based pretreatment IMRT
verification method will help to improve the quality assurance procedure.
Hintergrund:
Ein Electronic Portal Imaging Device (EPID) wird zur Kontrolle der Positionierung und Lagerung des Patienten während der fraktionierten
Strahlentherapie genutzt. Infolge der zunehmenden Komplexität und Konformität der Bestrahlungstechniken wächst auch die Forderung
einer genauen Verifikation der am Patienten applizierten Dosis. Das Ziel dieser Untersuchungen war die Ausarbeitung einer
einfachen Anleitung für die Dosimetrie mit einem Elekta iViewGTTM EPID mit kommerziellen Softwaremodulen.
Material und Methode:
Die Messungen wurden an einem Elektronenlinearbeschleuniger mit 6-MV-Photonenenergie der Firma Elekta, ausgestattet mit einem
iViewGTTM EPID, durchgeführt. Die Reproduzierbarkeit sowie die Eigenschaften des EPID-Signals in Abhängigkeit von der applizierten
Dosis, der Dosisleistung und der Feldgröße wurden untersucht. Eine Reihe von Experimenten, zum Vergleich des Ansprechvermögens
des EPIDs und Dosismessungen mit einer Ionisationskammer, bestimmen die Parameter für das Modell zur Kalibrierung. Außerdem
wurden die Messungen mit dem EPID mit Berechnungen des Bestrahlungsplanungssystems verglichen.
Ergebnisse:
Das EPID zeigt ein stabiles Ansprechvermögen über einen Zeitraum von 14 Monaten. Es wurde eine Nicht-Linearität in Abhängigkeit
von der applizierten Dosis von bis zu 6,8% festgestellt. Geringe Abweichungen von maximal 1,2% ergaben sich in Abhängigkeit
von der Dosisleistung. Für alle Felder stimmen die Ergebnisse für das kalibrierte EPID im Vergleich mit dem Bestrahlungsplanungssystem
mit Abweichungen von maximal 2–3% innerhalb des Feldes überein. In Regionen mit hohen Dosisgradienten ergaben sich größere
Abweichungen von bis zu 6%.
Schlussfolgerung:
Die Auswertung mit dem γ-Index ergibt eine gute Übereinstimmung der Ergebnisse, gemessen mit dem EPID im Vergleich zum Bestrahlungsplanungssystem.
Die Verifikation der IMRT-Dosisverteilung mit dem EPID wird die Qualitätssicherung verbessern.
Key WordsEPID dosimetry–Amorphous silicon EPID–IMRT verification–Dose response
SchlüsselwörterEPID-Dosimetrie–Amorphe Silizium-EPID–IMRT-Verifikation–Dosiswirkung
Strahlentherapie und Onkologie 04/2012; 187(5):316-321. · 3.56 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Background and aimsFor rectal carcinoma treated according to the concept of total mesorectal excision (TME surgery), the independent influence
of regional lymph node metastasis on the locoregional recurrence risk is still in discussion. A reliable assessment of this
risk is important for an individualised selective indication for neoadjuvant radio-/radiochemotherapy.
MethodsAnalysis of literature, especially of the last 20years, and consideration of pathological and oncological basic research.
Multivariate analysis of data of the Erlangen Registry of Colorectal Carcinoma.
ResultsThe clinical assessment of the pretherapeutic regional lymph node status by the present available imaging methods is still
unreliable. The analysis of the association between pretherapeutic regional lymph node status and locoregional recurrence
risk has to be based on follow-up data of patients treated by primary surgery and has to be distinguished between patients
treated by conventional and optimised quality-assured TME surgery, respectively. Data from Erlangen show an increase of the
local recurrence risk for patients with at least four involved regional lymph nodes.
ConclusionsFor patients with at least four involved regional lymph nodes, a neoadjuvant radiochemotherapy may be indicated. However,
today, the pretherapeutic diagnosis is uncertain and results in overtherapy in 40%. Thus, in case of positive lymph node findings
by imaging methods, the benefits and risk of neoadjuvant therapy in such situations should always be discussed with the patient
in the sense of informed consent and shared decision.
KeywordsLocal recurrence-Neoadjuvant treatment-Rectal carcinoma-Regional lymph node metastasis-TME (Total mesorectal excision) surgery
International Journal of Colorectal Disease 04/2012; 25(3):359-368. · 2.38 Impact Factor
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Claus Rödel,
Dirk Arnold,
Heinz Becker,
Rainer Fietkau,
Michael Ghadimi,
Ullrich Graeven,
Clemens Hess,
Ralf Hofheinz,
Werner Hohenberger,
Stefan Post,
Rudolf Raab,
Rolf Sauer,
Frederick Wenz,
Torsten Liersch
[show abstract]
[hide abstract]
ABSTRACT: Background:
In the era of preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), the development of distant
metastases is the predominant mode of failure in rectal cancer patients today. Integrating more effective systemic therapy
into combined modality programs is the challenge. The question that needs to be addressed is how and when to apply systemic
treatment with adequate dose and intensity.
Material and Methods:
This review article focuses on phase II–III trials designed to improve 5-fluorouracil (5-FU)-based combined
modality treatment for rectal cancer patients through the inclusion of concurrent, adjuvant or, most recently, induction
combination chemotherapy. Computerized bibliographic searches of PubMed were supplemented with hand searches of reference
lists and abstracts of ASCO/ASTRO/ESTRO meetings.
Results:
After preoperative CRT and surgical resection, approximately one third of patients do not receive adjuvant chemotherapy,
mainly due to surgical complications, patients’ refusal, or investigator’s discretion. In order to be able to apply chemotherapy
with sufficient dose and intensity, an innovative approach is to deliver systemic therapy prior to preoperative CRT rather
than
adjuvant chemotherapy. Emerging evidence from several phase II trials and, recently, randomized phase II trials indicate that
induction chemotherapy is feasible, does not compromise CRT or surgical resection, and enables the delivery of chemotherapy
in
adequate dose and intensity. Although this approach did not increase local efficacy in recent trials (e.g., pathological complete
response rates, tumor regression, R0 resection rates, local control), it may help to improve control of distant disease.
Conclusion:
Whether this improvement in applicability and dose density of chemotherapy will ultimately translate into improved
disease-free survival will have to be tested in a larger phase III trial.
Hintergrund:
Nach Einführung der präoperativen Radiochemotherapie (RCT) und der totalen mesoerektalen Excision manifestieren
sich Rezidive beim Rektumkarzinom am häufigsten als Fernmetastasen. Daher ist die Integration einer systemisch effektiveren
Therapie in das multimodale Behandlungskonzept derzeit die entscheidende Herausforderung. Die Frage ist, wann und wie
diese Systemtherapie mit adäquater Dosis und Intensität verabreicht werden kann.
Material und Methoden:
Der Übersichtsartikel beschreibt Phase II–III Studien, deren Ziel es war, die allein 5-FU-basierte
multimodale Behandlung durch Hinzunahme einer Kombinations-Chemotherapie, simultan zur Radiotherapie, adjuvant oder als
Induktionstherapie, zu verbessern. Dazu diente eine Suchabfrage in Pubmed, in Referenzlisten publizierter Arbeiten sowie Abstrakts
von ASCO/ASTRO/ESTRO-Konferenzen.
Ergebnisse:
Nach präoperativer RCT und Operation erhalten etwa ein Drittel aller Patienten wegen postoperativer Komplikationen,
patientenseitiger Ablehnung oder Entscheidung des betreuenden Arztes keine adjuvante Chemotherapie. Ein innovativer
Ansatz ist die Induktionschemotherapie vor präoperativer RCT und Operation, um die systemische Therapie in ausreichender
Dosierung und Intensität durchführen zu können. Eine Vielzahl an Phase II-Studien, und zuletzt auch randomisierter Phase-
II-Studien, zeigte, dass dieses Konzept durchführbar ist, die anschließende RCT und Operation nicht kompromittiert sowie die
systemische Komponente in adäquater Dosis und Intensität applizierbar macht. Wenngleich dadurch die lokale Wirksamkeit
(histopathologisch bestätigte Komplettremission, Tumorregression, R0-Resektionsrate, lokale Kontrolle) nicht verbessert wurde,
könnte sich dieses Vorgehen positiv auf die systemische Tumorkontrolle auswirken.
Schlussfolgerung:
Eine Phase-III-Studie muss klären, ob die verbesserte Durchführbarkeit und Dosisdichte einer Induktionschemotherapie
das krankheitsfreie Überleben verbessern kann.
Key WordsRectal cancer–Induction chemotherapy–Chemoradiotherapy
SchlüsselwörterRektumkarzinom–Induktionschemotherapie–Radiochemotherapie
Strahlentherapie und Onkologie 04/2012; 186(12):658-664. · 3.56 Impact Factor
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Rolf Sauer,
Torsten Liersch,
Susanne Merkel,
Rainer Fietkau,
Werner Hohenberger,
Clemens Hess,
Heinz Becker,
Hans-Rudolf Raab,
Marie-Therese Villanueva,
Helmut Witzigmann,
Christian Wittekind,
Tim Beissbarth, Claus Rödel
[show abstract]
[hide abstract]
ABSTRACT: Preoperative chemoradiotherapy (CRT) has been established as standard treatment for locally advanced rectal cancer after first results of the CAO/ARO/AIO-94 [Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society] trial, published in 2004, showed an improved local control rate. However, after a median follow-up of 46 months, no survival benefit could be shown. Here, we report long-term results with a median follow-up of 134 months.
A total of 823 patients with stage II to III rectal cancer were randomly assigned to preoperative CRT with fluorouracil (FU), total mesorectal excision surgery, and adjuvant FU chemotherapy, or the same schedule of CRT used postoperatively. The study was designed to have 80% power to detect a difference of 10% in 5-year overall survival as the primary end point. Secondary end points included the cumulative incidence of local and distant relapses and disease-free survival.
Of 799 eligible patients, 404 were randomly assigned to preoperative and 395 to postoperative CRT. According to intention-to-treat analysis, overall survival at 10 years was 59.6% in the preoperative arm and 59.9% in the postoperative arm (P = .85). The 10-year cumulative incidence of local relapse was 7.1% and 10.1% in the pre- and postoperative arms, respectively (P = .048). No significant differences were detected for 10-year cumulative incidence of distant metastases (29.8% and 29.6%; P = .9) and disease-free survival.
There is a persisting significant improvement of pre- versus postoperative CRT on local control; however, there was no effect on overall survival. Integrating more effective systemic treatment into the multimodal therapy has been adopted in the CAO/ARO/AIO-04 trial to possibly reduce distant metastases and improve survival.
Journal of Clinical Oncology 04/2012; 30(16):1926-33. · 18.37 Impact Factor
