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Purpose: The optimal treatment of stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined. Thus, we performed an analysis using the database of the German Hodgkin Study Group., Patients and Methods: The long-term outcome of 256 patients with stage IA NLPHL was evaluated. Patients had received combined-modality treatment (CMT; n = 72), extended-field radiotherapy (EF-RT; n = 49), involved-field radiotherapy (IF-RT; n = 108), or four weekly standard doses of rituximab (n = 27) within German Hodgkin Study Group clinical trial protocols between 1988 and 2009., Results: The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Most patients were male (76%). The whole patient group had a median follow-up of 91 months (CMT: 95 months; EF-RT: 110 months; IF-RT: 87 months; rituximab: 49 months). At 8 years, progression-free survival and overall survival rates were 88.5% and 98.6% for CMT, 84.3% and 95.7% for EF-RT, and 91.9% and 99.0% for IF-RT, respectively. Patients treated with rituximab had 4-year progression-free and overall survival rates of 81.0% and 100%, respectively. A second malignancy during the course of follow-up was diagnosed in 17 (6.6%) of 256 patients. A total of 12 deaths occurred. However, only one patient died from NLPHL., Conclusion: Tumor control in this analysis was equivalent with CMT, EF-RT, and IF-RT. Therefore, IF-RT, which is associated with the lowest risk for the development of toxic effects, should be considered as standard of care for patients with stage IA NLPHL. Rituximab alone is associated with an increased risk of relapse in this patient population., (© 2015 by American Society of Clinical Oncology.)

Background: The registry for the evaluation of side effects after radiotherapy in childhood and adolescence (RiSK) was established to prospectively characterize radiation-associated side effects. The purpose of this analysis was to characterize side effects after radiotherapy to the head and neck in children and adolescents., Methods: Radiation doses have been collected across Germany since 2001. Acute and late side effects were characterized., Results: Until January 2010, 133 patients (median age, 12.7 years) were recruited who had received radiotherapy to the salivary glands. Toxicity evaluation was available for 114 patients (median follow-up, 2.9 years). Acute and late toxicity significantly depended on the maximum radiation dose to the salivary glands. An increase of the mean value of maximum dose of 1 Gray (Gy) to the submandibular glands resulted in an odds ratio of 1.04 (range, 1.00-1.08; p = .039) for acute toxicities of the salivary glands and 1.08 (range, 1.03-1.13; p = .001) for acute mucosal toxicities., Conclusion: These data can be used for an individual risk assessment in pediatric head and neck radiotherapy., (© 2014 Wiley Periodicals, Inc.)

Background and Purpose: Radiation therapy (RT) is an established and effective treatment modality in the management of a large variety of hyperproliferative disorders and benign neoplasms. Objective of this article is to summarize the updated DEGRO consensus S2e guideline recommendations., Materials and Methods: This report comprises an overview of the relevant aspects of the updated guidelines with regard to treatment decision, dose prescription, and RT technique for a selected group of disorders including Morbus Dupuytren (MD)/Morbus Ledderhose (ML), keloids, Peyronie's disease (induratio penis plastica, IPP), desmoid tumors, pigmented villonodular synovitis (PVNS), symptomatic vertebral hemangiomas (sVH), and Gorham-Stout syndrome (GSS). On the basis of results in the literature, we attempted to classify the level of evidence (LoE) and the grade of recommendation (GR) according to the Oxford criteria., Results: There is comprehensive evidence in the literature that RT is a reasonable and effective treatment modality for the treatment of all the above-mentioned disorders. The LoE varies from 2c to 4, and GR varies from A to C., Conclusions: The use of RT can be recommended for the interdisciplinary management of most of the reported disorders. It can be used in the primary treatment approach and as an effective adjunct to other treatment modalities or in some indications as a valuable alternative treatment option. We hope that the updated DEGRO S2e consensus guideline recommendations are a helpful tool for radiation oncologists in the clinical decision-making process.

Background: Recent evidence suggests that ionizing radiation may be associated with unexpected side-effects in melanoma patients treated with concomitant BRAF inhibitors. A large multicenter analysis was carried out to generate reliable safety data and elucidate the mechanism., Methods: A total of 161 melanoma patients from 11 European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence in situ hybridization of chromosomal breaks after ex vivo irradiation., Results: With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis ≥2° was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole-brain radiotherapy, rates of radiodermatitis ≥2° were 44% and 8% (P < 0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis ≥2° more frequently than treatment with dabrafenib (40% versus 26%, P = 0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (P = 0.004) and for patients switched from vemurafenib to dabrafenib (P = 0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment., Conclusion: Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Exophthalmos, myxedema and osteoarthropathy (EMO) comprise the triad known as EMO syndrome, which is rarely observed in patients with autoimmune thyroid disease. The present study reports the case of a patient with EMO, including the response of this rare combination to radiotherapy. A 48-year-old patient with EMO syndrome presented to the Department of Radiation Oncology, University Hospital of Muenster, eight years prior to writing with therapy-resistant pretibial myxedema and hypertrophic osteoarthropathy of the metacarpal bones. The patient had been diagnosed with Graves' disease (GD) 26 years prior to presentation, which was treated by thyroidectomy and radioiodine therapy. Four years subsequent to the diagnosis of GD, the patient developed exophthalmos, which was treated using radiotherapy. An evident pretibial, foot and hand myxedema developed within the 10 years following the onset of orbitopathy. The skin lesions were treated using radiation therapy subsequent to the failure of multiple surgical procedures and medical treatments. Almost eight years subsequent to the administration of irradiation, no recurrence was observed on the lower right leg, nor was any recurrence on the lower left leg observed approximately four years subsequent to the completion of radiotherapy. However, an additional lesion on the left hand demonstrated slow progression following treatment with radiation therapy. The present study indicates that radiation therapy can be considered as adjuvant therapy for patients with refractory myxedema, to prevent or delay the recurrence of myxedema subsequent to surgical excision.

Aim: The aim of this study was to evaluate acute and late radiotherapy-associated hepatotoxicity in consideration of dose-volume effects and liver function in childhood and adolescence., Patients and Methods: Since 2001, irradiated children and adolescents in Germany have been prospectively documented in the "Register of Treatment-Associated Late Effects After Radiotherapy of Malignant Diseases in Childhood and Adolescence (RiSK)" using standardized forms. Toxicity was graded according to the Radiation Therapy Oncology Group (RTOG) criteria., Results: Until April 2012, 1,392 children and adolescents from 62 radiotherapy centers were recruited. In all, 216 patients underwent irradiation of the liver (median age 9 years, range 1-18 years, 70 patients with total-body irradiation, TBI). For 75 % of patients without TBI, information on acute toxicity of the liver was available: 24 patients had acute toxicity of grade 1-4 (grade 1, 2, and 4, in 20, 3, and 1 patient, respectively), including five patients receiving simultaneous hepatotoxic chemotherapy. Information on late toxicity was documented in 465 forms from 216 patients, with a median follow-up of 2 years. A maximum grade of toxicity of ≥ 0 occurred in 18 patients over time (with grade 1, 2, and 3 toxicity occurring in 15, 2, and 1 patient, respectively), including three patients (17 %) with TBI. One of them received simultaneous hepatotoxic chemotherapy. In multivariable analysis, volume-dose correlations showed no statistically noticeable effect on acute or chronic toxicity., Conclusion: Only low hepatotoxicity developed in children after irradiation of various abdominal and thoracic tumors. Due to the low radiation doses to the liver (median liver dose = 5 Gy) and the low toxicities that were consecutively observed, dose-volume curves for liver toxicity could not be established. These findings reflect the cautious attitude of radiation oncologists in terms of attributable liver doses in the treatment of the investigated tumor entities. It offers the option of increasing these conservative doses if tumor control is necessary.

Purpose: To determine, in the setting of advanced-stage of Hodgkin lymphoma (HL), whether relapses occur in the irradiated planning target volume and whether the definition of local radiation therapy (RT) used by the German Hodgkin Study Group (GHSG) is adequate, because there is no harmonization of field and volume definitions among the large cooperative groups in the treatment of advanced-stage HL., Methods and Materials: All patients with residual disease of ≥ 2.5 cm after multiagent chemotherapy (CTX) were evaluated using additional positron emission tomography (PET), and those with a PET-positive result were irradiated with 30 Gy to the site of residual disease. We re-evaluated all sites of disease before and after CTX, as well as the PET-positive residual tumor that was treated in all relapsed patients. Documentation of radiation therapy (RT), treatment planning procedures, and portal images were carefully analyzed and compared with the centrally recommended RT prescription. The irradiated sites were compared with sites of relapse using follow-up computed tomography scans., Results: A total of 2126 patients were enrolled, and 225 patients (11%) received RT. Radiation therapy documents of 152 irradiated patients (68%) were analyzed, with 28 irradiated patients (11%) relapsing subsequently. Eleven patients (39%) had an in-field relapse, 7 patients (25%) relapsed outside the irradiated volume, and an additional 10 patients (36%) showed mixed in- and out-field relapses. Of 123 patients, 20 (16%) with adequately performed RT relapsed, compared with 7 of 29 patients (24%) with inadequate RT., Conclusions: The frequency and pattern of relapses suggest that local RT to PET-positive residual disease is sufficient for patients in advanced-stage HL. Insufficient safety margins of local RT may contribute to in-field relapses., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We present a case of radiotherapy for a 66-year-old patient with squamous cell carcinoma on the left main bronchus undergoing implantation of pacemaker, implantable cardioverter defibrillator (ICD) as well as cardiopulmonary support (CPS) device. The radiation area was determined according to 4D List Mode positron emission tomography-computed tomography (PET-CT) data. Planning Target Volume (PTV) included a part of the active ICD. For the optimal tumor coverage and sparing of both the implantable cardiac devices and organs at risk, we combined the conformal radiotherapy with stereotactic body radiotherapy (SBRT) using helical tomotherapy. The prescription dose of 25.2Gy was applied by conventional radiotherapy. SBRT was performed hypofractionated with a prescription dose of 35Gy in 5 fractions. A dynamic electrocardiogram was performed during every radiation fraction. The implanted aggregates were checked three times a week. Despite partial localization of the active ICD in the radiation field, the tumor was treated without inappropriate shock delivery during radiation treatment and over twelve months afterwards. The reduced tumor size as well as tumor metabolic activity were observed by PET-CT three months after radiation treatment. The patient exhibited no signs of pneumonitis on the last radiological follow-up examination six months after radiotherapy. The reduced dyspnea and cough over the first four months after treatment were observed.In conclusion, tumor shrinkage and temporary clinical improvement of the patient as well as no technical complications of implanted cardiac devices were achieved by the radiation treatment.

Purpose: To summarize the updated DEGRO consensus S2e guideline recommendations for the treatment of benign symptomatic functional disorders with low-dose radiotherapy., Materials and Methods: This overview reports on the role of low-dose radiotherapy in the treatment of functional disorders in cases of heterotopic ossification (HO) and Graves orbitopathy (GO). The most relevant aspects of the DEGRO S2e Consensus Guideline "Radiation Therapy of Benign Diseases 2014" regarding diagnostics, treatment decision, dose prescription, as well as performance of radiotherapy and results are summarized., Results: For both indications (HO, GO), retrospective and some prospective analyses have shown remarkable effects in terms of symptom relief. Nevertheless, the level of evidence (LoE) and the grade of recommendation (GR) vary: LoE 1-2 and GR A-B (HO), LoE 2 and GR B (GO)., Conclusion: Low-dose radiotherapy for benign symptomatic functional disorders has proven to be effective, according to different authors, for 25-100 % of the patients studied and therefore it may be a reasonable prophylactic and therapeutic option if noninvasive or invasive methods have been used without persistent success. For HO, a single-fraction dose of 7-8 Gy or fractionated radiation with five fractions of 3.5 Gy is recommended. For GO, single-fraction doses of 0.3-2.0 Gy, and total doses of 2.4-20 Gy/series, applied in one daily fraction are recommended.

Unlabelled: The aim was to analyze the degree of agreement between the central review panel and the local PET interpretation within the HD15 trial and its impact on subsequent treatment and progression free survival., Patients, Methods: The analysis set consisted of 739 patients with residues ≥ 2.5 cm after 6 or 8 cycles of BEACOPPesc from the HD15 trial performed by the German Hodgkin Study Group. The recommendation for or against further radiotherapy was based on the central [(18)F]FDG-PET interpretation. Central PET interpretation was compared to the local PET interpretation and concordance was measured using Cohen's Kappa coefficient. Prognostic impact of the analysis of concordance between local and central PET interpretations was evaluated using progression free survival (PFS); groups were compared with the log rank test., Results: The central panel rated 548 of 739 patients (74%) as PET negative. Of these, 513 were also rated as PET negative in the local PET interpretation. PET positivity was seen by central reviewers in the remaining 191 patients (26%), in concordance with local reviewers in 155 cases. Even though substantial agreement was found (Cohen's Kappa 0.81), the interpretation of the central PET review panel led to a different therapeutic recommendation in 71/739 (10%) patients. PFS was equally high in groups in which the therapeutic regime had been changed on the basis of the central panel decision., Conclusion: High concordance is found between local and central reviewers with regard to PET interpretation in residual tissue after intense chemotherapy. The existence of the central PET review panel allows the identification of additional patients as PET negative so that radiotherapy can be safely omitted (35 of 548 patients = 4.7%).

Purpose: In 2010, we reported that selenium (Se) supplementation during radiation therapy (RT) is effective for increasing blood Se levels in Se-deficient cervical and uterine cancer patients, and reduced the number of episodes and severity of RT-induced diarrhea. In the current study, we examine whether of Se supplementation during adjuvant RT affects long-term survival of these patients., Patients and Methods: Former patients were identified and questioned with respect to their health and well-being., Results: A total of 81 patients were randomized in the initial supplementation study, 39 of whom received Se (selenium group, SeG) and 42 of whom served as controls (control group, CG). When former patients were reidentified after a median follow-up of 70 months (range = 0-136), the actuarial 10-year disease-free survival rate in the SeG was 80.1% compared to 83.2% in the CG (P = .65), and the actuarial 10-year overall survival rate of patients in the SeG was 55.3% compared to 42.7% in the CG (P = .09)., Conclusions: Our extended follow-up analysis demonstrates that Se supplementation had no influence on the effectiveness of the anticancer irradiation therapy and did not negatively affect patients' long-term survival. In view of its positive effects on RT-induced diarrhea, we consider Se supplementation to be a meaningful and beneficial adjuvant treatment in Se-deficient cervical and uterine cancer patients while undergoing pelvic radiation therapy., (© The Author(s) 2014.)

Background and Purpose: Physical 3D treatment planning provides a pool of parameters describing dose distributions. It is often useful to define conformal indices to enable quicker evaluation. However, the application of individual indices is controversial and not always effective. The aim of this study was to design a quick check of dose distributions based on several indices detecting underdosages within planning target volumes (PTVs) and overdosages in normal tissue., Materials and Methods: Dose distributions of 215 cancer patients were considered. Treatment modalities used were three-dimensional conformal radiotherapy (3DCRT), radiosurgery, intensity-modulated radiotherapy (IMRT), intensity-modulated arc therapy (IMAT) and tomotherapy. The volumes recommended in ICRU 50 and 83 were used for planning and six conformation and homogeneity indices were selected: CI, CN, CICRU, COV, C∆, and HI. These were based on the PTV, the partial volume covered by the prescribed isodose (PI; PTVPI), the treated volume (TVPI), near maximum D2 and near minimum D98. Results were presented as a hexagon-the corners of which represent the values of the indices-and a modified test function F (Rosenbrock's function) was calculated. Results refer to clinical examples and mean values, in order to allow evaluation of the power of F and hexagon-based decision support procedures in detail and in general., Results: IMAT and tomotherapy showed the best values for the indices and the lowest standard deviation followed by static IMRT. DCRT and radiosurgery (e.g. CN: IMAT 0.85 ± 0.06; tomotherapy 0.84 ± 0.06; IMRT 0.83 ± 0.07; 3DCRT 0.65 ± 0.08; radiosurgery 0.64 ± 0.11). In extreme situations, not all indices reflected the situation correctly. Over- and underdosing of PTV and normal tissue could be qualitatively assessed from the distortion of the hexagon in graphic analysis. Tomotherapy, IMRT, IMAT, 3DCRT and radiosurgery showed increasingly distorted hexagons, the type of distortion indicating exposure of normal tissue volumes. The calculated F values correlated with these observations., Conclusion: An evaluation of dose distributions cannot be based on a single conformal index. A solution could be the use of several indices presented as a hexagonal graphic and/or as a test function.

Purpose: Hodgkin lymphoma (HL) is a highly curable disease. Reducing late complications and second malignancies has become increasingly important. Radiotherapy target paradigms are currently changing and radiotherapy techniques are evolving rapidly., Design: This overview reports to what extent target volume reduction in involved-node (IN) and advanced radiotherapy techniques, such as intensity-modulated radiotherapy (IMRT) and proton therapy-compared with involved-field (IF) and 3D radiotherapy (3D-RT)- can reduce high doses to organs at risk (OAR) and examines the issues that still remain open., Results: Although no comparison of all available techniques on identical patient datasets exists, clear patterns emerge. Advanced dose-calculation algorithms (e.g., convolution-superposition/Monte Carlo) should be used in mediastinal HL. INRT consistently reduces treated volumes when compared with IFRT with the exact amount depending on the INRT definition. The number of patients that might significantly benefit from highly conformal techniques such as IMRT over 3D-RT regarding high-dose exposure to organs at risk (OAR) is smaller with INRT. The impact of larger volumes treated with low doses in advanced techniques is unclear. The type of IMRT used (static/rotational) is of minor importance. All advanced photon techniques result in similar potential benefits and disadvantages, therefore only the degree-of-modulation should be chosen based on individual treatment goals. Treatment in deep inspiration breath hold is being evaluated. Protons theoretically provide both excellent high-dose conformality and reduced integral dose., Conclusion: Further reduction of treated volumes most effectively reduces OAR dose, most likely without disadvantages if the excellent control rates achieved currently are maintained. For both IFRT and INRT, the benefits of advanced radiotherapy techniques depend on the individual patient/target geometry. Their use should therefore be decided case by case with comparative treatment planning.

Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment. The role of reduced volumes and doses is addressed, integrating modern imaging with 3-dimensional (3D) planning and advanced techniques of treatment delivery. The previously applied extended field (EF) and original involved field (IF) techniques, which treated larger volumes based on nodal stations, have now been replaced by the use of limited volumes, based solely on detectable nodal (and extranodal extension) involvement at presentation, using contrast-enhanced computed tomography, positron emission tomography/computed tomography, magnetic resonance imaging, or a combination of these techniques. The International Commission on Radiation Units and Measurements concepts of gross tumor volume, clinical target volume, internal target volume, and planning target volume are used for defining the targeted volumes. Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control. The highly conformal involved node radiation therapy (INRT), recently introduced for patients for whom optimal imaging is available, is explained. A new concept, involved site radiation therapy (ISRT), is introduced as the standard conformal therapy for the scenario, commonly encountered, wherein optimal imaging is not available. There is increasing evidence that RT doses used in the past are higher than necessary for disease control in this era of combined modality therapy. The use of INRT and of lower doses in early-stage HL is supported by available data. Although the use of ISRT has not yet been validated in a formal study, it is more conservative than INRT, accounting for suboptimal information and appropriately designed for safe local disease control. The goal of modern smaller field radiation therapy is to reduce both treatment volume and treatment dose while maintaining efficacy and minimizing acute and late sequelae. This review is a consensus of the International Lymphoma Radiation Oncology Group (ILROG) Steering Committee regarding the modern approach to RT in the treatment of HL, outlining a new concept of ISRT in which reduced treatment volumes are planned for the effective control of involved sites of HL. Nodal and extranodal non-Hodgkin lymphomas (NHL) are covered separately by ILROG guidelines., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Positron emission tomography (PET) after chemotherapy can guide consolidating radiotherapy in advanced-stage Hodgkin lymphoma (HL). This analysis aims to improve outcome prediction by integrating additional criteria derived by computed tomography (CT)., Patients and Methods: The analysis set consisted of 739 patients with residues≥2.5 cm after chemotherapy from a total of 2,126 patients treated in the HD15 trial (HD15 for advanced stage Hodgkin's disease: Quality assurance protocol for reduction of toxicity and the prognostic relevance of fluorodeoxyglucose-positron-emission tomography [FDG-PET] in the first-line treatment of advanced-stage Hodgkin's disease) performed by the German Hodgkin Study Group. A central panel performed image analysis and interpretation of CT scans before and after chemotherapy as well as PET scans after chemotherapy. Prognosis was evaluated by using progression-free survival (PFS); groups were compared with the log-rank test. Potential prognostic factors were investigated by using receiver operating characteristic analysis and logistic regression., Results: In all, 548 (74%) of 739 patients had PET-negative residues after chemotherapy; these patients did not receive additional radiotherapy and showed a 4-year PFS of 91.5%. The 191 PET-positive patients (26%) receiving additional radiotherapy had a 4-year PFS of 86.1% (P=.022). CT alone did not allow further separation of patients in partial remission by risk of recurrence (P=.9). In the subgroup of the 54 PET-positive patients with a relative reduction of less than 40%, the risk of progression or relapse within the first year was 23.1% compared with 5.3% for patients with a larger reduction (difference, 17.9%; 95% CI, 5.8% to 30%)., Conclusion: Patients with HL who have PET-positive residual disease after chemotherapy and poor tumor shrinkage are at high risk of progression or relapse., (© 2014 by American Society of Clinical Oncology.)

Background: Desmoids (aggressive fibromatosis) are defined as benign neoplasms of the connective tissue that arise from the deep muscle fascia, aponeurosis, tendons, and scar tissue. Recurrence rates between 40 and 80% were reported after surgery alone. We addressed the impact of radiation therapy (RT) in the management of aggressive fibromatosis., Patients and Methods: A large literature review was performed, and the data was compared with the results of a multicenter study of the German Cooperative Group on Radiotherapy for Benign Diseases (GCG-BD)., Results: This analysis included 52 patients treated with RT. 37 patients received postoperative RT (20 patients after R2 resection and 17 patients after R1 resection). 15 patients received RT alone (6 patients with inoperable primary tumor and 9 patients with inoperable recurrent tumor). In the case of postoperative RT, a median dose of 50 Gy (range 50-60 Gy) was used; for definitive RT, a median dose of 55 Gy (range 55-65 Gy) was used. The local control rate was 79% for the whole group. The median follow-up was 44 month (range 8-62 months)., Conclusion: Given the large number of patients, these data show that RT is highly effective in the treatment of desmoid tumors. RT is an attractive alternative to mutilating surgery.

Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a coreceptor for growth factors and chemokines and is a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of Syndecan-1-deficient mice to experimentally-induced tumorigenesis has been linked to altered Wnt-responsive precursor cell pools, suggesting a potential role of Syndecan-1 in breast cancer cell stem function. However, the precise molecular mechanism is still elusive. Here, we decipher the functional impact of Syndecan-1 knockdown using RNA interference on the breast cancer stem cell phenotype of human triple-negative MDA-MB-231 and hormone receptor-positive MCF-7 cells in vitro employing an analytical flow cytometric approach. Successful Syndecan-1 siRNA knockdown was confirmed by flow cytometry. Side population measurement by Hoechst dye exclusion and Aldehyde dehydrogenase-1 activity revealed that Syndecan-1 knockdown in MDA-MB-231 cells significantly reduced putative cancer stem cell pools by 60% and 27%, respectively, compared to controls. In MCF-7 cells, Syndecan-1 depletion reduced the side population by 40% and Aldehyde dehydrogenase-1 by 50%, repectively. In MDA-MB-231 cells, the CD44(+)CD24(-/low) phenotype decreased significantly by 6% upon siRNA-mediated Syndecan-1 depletion. Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated by >40% in Syndecan-1-silenced MDA-MB-231 cells, which showed a dysregulated response to IL-6-induced shifts in E-cadherin and vimentin expression. Furthermore, activation of STAT-3 and NFkB transcription factors and expression of a coreceptor for Wnt signaling, LRP-6, were reduced by >45% in Syndecan-1-depleted cells compared to controls. At the functional level, Syndecan-1 siRNA reduced the formation of spheres and cysts in MCF-7 cells grown in suspension culture. Our study demonstrates the viability of flow cytometric approaches in analyzing cancer stem cell function. As Syndecan-1 modulates the cancer stem cell phenotype via regulation of the Wnt and IL-6/STAT3 signaling pathways, it emerges as a promising novel target for therapeutic approaches.

Background: In early-stage Hodgkin's lymphoma (HL), treatment according to the early favorable or unfavorable subgroup is guided by staging definitions, which differ between various study groups worldwide. We analyzed risk factors used in different international staging systems and their impact on the outcome of early-stage HL patients., Patients and Methods: In 1173 early-stage HL patients treated homogenously within the German Hodgkin Study Group (GHSG) trials HD10 and HD11, the impact of three staging systems developed and used by the GHSG, the European Organization for Research and Treatment of Cancer (EORTC), and the National Comprehensive Cancer Network (NCCN) in discriminating risk groups for progression-free survival (PFS) and overall survival (OS) was assessed and the relevance of their single risk factors was investigated., Results: All the three staging systems defined an unfavorable risk group out of early-stage patients of comparable size (56%, 55%, and 57%), having a significantly poorer PFS and OS as compared with the corresponding favorable group; 5-year differences between early favorable and early unfavorable in terms of PFS were 9.4% (HR 2.61, 95% CI 1.74-3.91), 6.7% (HR 2.10, 95% CI 1.41-3.13), and 8.6% (HR 2.14, 95% CI 1.45-3.16) with the GHSG, EORTC, and NCCN definition, respectively. Sensitivity was high for all systems (84%, 79%, and 83%); however, there was a low specificity with high rates of false-positive results (1-specificity 54%, 53%, and 55%, respectively). Models of high sensitivity included risk factors associated with large tumor burden and high tumor activity. Most risk factors for tumor-specific end points were also predictive of OS., Conclusions: Differentiating between a favorable and an unfavorable risk group has significant impact on PFS and OS in early-stage HL patients in the modern treatment era. Risk-adapted treatment strategies using new risk factors with higher specificity are needed.

Background: Treatment options for patients with nonbulky stage IA-IIA Hodgkin lymphoma include combined modality therapy (CMT) using doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus involved-field radiation therapy (IFRT), and chemotherapy with ABVD alone. There are no mature randomized data comparing ABVD with CMT using modern radiation techniques., Patients and Methods: Using German Hodgkin Study Group HD10/HD11 and NCIC Clinical Trials Group HD.6 databases, we identified 588 patients who met mutually inclusive eligibility criteria from the preferred arms of HD10 or 11 (n = 406) and HD.6 (n = 182). We evaluated time to progression (TTP), progression-free (PFS) and overall survival, including in three predefined exploratory subset analyses., Results: With median follow-up of 91 (HD10/11) and 134 (HD.6) months, respective 8-year outcomes were for TTP, 93% versus 87% [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.24-0.78]; for PFS, 89% versus 86% (HR 0.71, 95% CI 0.42-1.18) and for overall survival, 95% versus 95% (HR 1.09, 95% CI 0.49-2.40). In the exploratory subset analysis including HD10 eligible patients who achieved complete response (CR) or unconfirmed complete response (CRu) after two cycles of ABVD, 8-year PFS was 87% (HD10) versus 95% (HD.6) (HR 2.8; 95% CI 0.64-12.5) and overall survival 96% versus 100%. In contrast, among those without CR/CRu after two cycles of ABVD, 8-year PFS was 88% versus 74% (HR 0.35; 95% CI 0.16-0.79) and overall survival 95% versus 91%, respectively (HR 0.42; 95% CI 0.12-1.44)., Conclusions: In patients with nonbulky stage IA-IIA Hodgkin lymphoma, CMT provides better disease control than ABVD alone, especially among those not achieving complete response after two cycles of ABVD. Within the follow-up duration evaluated, overall survivals were similar. Longer follow-up is required to understand the implications of radiation and chemotherapy-related late effects., Clinical Trials: The trials included in this analysis were registered at ClinicalTrials.gov: HD10 - NCT00265018, HD11 - NCT00264953, HD.6 - NCT00002561.

Introduction: Langerhans Cell Histiocytosis (LCH) represents a rare benign disorder, previously designated as "Histiocytosis X", "Type II Histiocytosis" or "Langerhans Cell Granulomatosis". Clinical presentation includes osteolysis, ulcerations of skin and soft tissues but also involvement of the CNS is described.Because treatment concepts are not well defined the German Cooperative Group on Radiotherapy for Benign Diseases performed a retrospective analysis., Methods and Material: Eight closely cooperating centres collected patients' data of the past 45 years. As study endpoints disease free survival, recurrent disease, death and therapy related side effects were defined., Results: A total of 80 patients with histologically proven LCH were irradiated within the past 45 years. According to the LCH classification of Greenberger et al. 37 patients had stage Ia, 21 patients stage Ib, 13 patients stage II and 9 patients stage IIIb and the median age was 29 years. The median Follow up was 54 months (range 9-134 months). A total of 39 patients had a surgical intervention and 23 patients a chemotherapy regimen.Radiation treatment was carried out with a median total dose of 15 Gy (range 3-50.4 Gy). The median single fraction was 2 Gy (range 1.8-3 Gy).Overall, 77% patients achieved a complete remission and 12.5% achieved a partial remission. The long-term control rate reached 80%. Within an actuarial overall 5-year survival of 90% no radiogenic side and late effects ≥EORTC/RTOG II° were observed., Conclusion: In the present study a large collective of irradiated patients was analysed. Radiotherapy (RT) is a very effective and safe treatment option and even low RT doses show sufficient local control.

This report reviews aspects of the German evidence-based guidelines for Hodgkin's lymphoma relevant to radiation oncologists. Stage-adapted treatment is discussed with the focus on radiotherapy. Up-to-date literature citations provide an overview of current recommendations.

Purpose: Older patients with Hodgkin lymphoma (HL) account for approximately 20% of all HL patients. ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy is regarded as standard of care in these patients. However, little is known on feasibility and efficacy of ABVD in this age group., Patients and Methods: We analyzed the feasibility and efficacy of four cycles of ABVD in older patients age 60 to 75 years with early-stage HL who were treated within the German Hodgkin Study Group (GHSG) HD10 and HD11 trials; results were compared with those of younger patients treated within these trials., Results: In total, 1,299 patients received four cycles of ABVD, and 117 of those patients were older than age 60 years (median, 65 years). In 14% of older patients, treatment was not administered according to protocol, mainly because of excessive toxicity. The mean delay of treatment was twice as high in the older patients (2.2 v 1.2 weeks). Fifty-nine percent of older patients achieved a relative dose-intensity of at least 80% compared with 85% of younger patients. Major toxicity (WHO grade 3 and 4), including leucopenia, nausea, infection, and others, was documented in 68% of older patients with a treatment-related mortality of 5%. Complete response was achieved in 89% of older patients, 3% had progressive disease, and 11% relapsed. At a median observation time of 92 months, 28% of the patients had died, and the 5-year progression-free survival estimate was 75% (95% CI, 66% to 82%)., Conclusion: In patients age ≥ 60 years with HL, four cycles of ABVD is associated with substantial dose reduction, treatment delay, toxicity, and treatment-related mortality.

Purpose: The goal of the present work was to assess the potential advantage of intensity-modulated radiotherapy (IMRT) over three-dimensional conformal radiotherapy (3D-CRT) planning in pelvic Ewing's sarcoma., Patients and Methods: A total of 8 patients with Ewing sarcoma of the pelvis undergoing radiotherapy were analyzed. Plans for 3D-CRT and IMRT were calculated for each patient. Dose coverage of the planning target volume (PTV), conformity and homogeneity indices, as well as further parameters were evaluated., Results: The average dose coverage values for PTV were comparable in 3D-CRT and IMRT plans. Both techniques had a PTV coverage of V95 > 98 % in all patients. Whereas the IMRT plans achieved a higher conformity index compared to the 3D-CRT plans (conformity index 0.79 ± 0.12 vs. 0.54 ± 0.19, p = 0.012), the dose distribution across the target volumes was less homogeneous with IMRT planning than with 3D-CRT planning. This difference was statistically significant (homogeneity index 0.11 ± 0.03 vs. 0.07 ± 0.0, p = 0.035). For the bowel, Dmean and D1%, as well as V2 to V60 were reduced in IMRT plans. For the bladder and the rectum, there was no significant difference in Dmean. However, the percentages of volumes receiving at least doses of 30, 40, 45, and 50 Gy (V30 to V50) were lower for the rectum in IMRT plans. The volume of normal tissue receiving at least 2 Gy (V2) was significantly higher in IMRT plans compared with 3D-CRT, whereas at high dose levels (V30) it was significantly lower., Conclusion: Compared to 3D-CRT, IMRT showed significantly better results regarding dose conformity (p = 0.012) and bowel sparing at dose levels above 30 Gy (p = 0.012). Thus, dose escalation in the radiotherapy of pelvic Ewing's sarcoma can be more easily achieved using IMRT.

Purpose: Respiratory gating is an established approach to overcoming respiration-induced image artefacts in PET. Of special interest in this respect are raw PET data-driven gating methods which do not require additional hardware to acquire respiratory signals during the scan. However, these methods rely heavily on the quality of the acquired PET data (statistical properties, data contrast, etc.). We therefore combined external radioactive markers with data-driven respiratory gating in PET/CT. The feasibility and accuracy of this approach was studied for [(18)F]FDG PET/CT imaging in patients with malignant liver and lung lesions., Methods: PET data from 30 patients with abdominal or thoracic [(18)F]FDG-positive lesions (primary tumours or metastases) were included in this prospective study. The patients underwent a 10-min list-mode PET scan with a single bed position following a standard clinical whole-body [(18)F]FDG PET/CT scan. During this scan, one to three radioactive point sources (either (22)Na or (18)F, 50-100 kBq) in a dedicated holder were attached the patient's abdomen. The list mode data acquired were retrospectively analysed for respiratory signals using established data-driven gating approaches and additionally by tracking the motion of the point sources in sinogram space. Gated reconstructions were examined qualitatively, in terms of the amount of respiratory displacement and in respect of changes in local image intensity in the gated images., Results: The presence of the external markers did not affect whole-body PET/CT image quality. Tracking of the markers led to characteristic respiratory curves in all patients. Applying these curves for gated reconstructions resulted in images in which motion was well resolved. Quantitatively, the performance of the external marker-based approach was similar to that of the best intrinsic data-driven methods. Overall, the gain in measured tumour uptake from the nongated to the gated images indicating successful removal of respiratory motion was correlated with the magnitude of the respiratory displacement of the respective tumour lesion, but not with lesion size., Conclusion: Respiratory information can be assessed from list-mode PET/CT through PET data-derived tracking of external radioactive markers. This information can be successfully applied to respiratory gating to reduce motion-related image blurring. In contrast to other previously described PET data-driven approaches, the external marker approach is independent of tumour uptake and thereby applicable even in patients with poor uptake and small tumours.

Background: In a previous analysis (Int J Radiat Oncol Biol Phys 70:828-835,2010), we assessed whether an adjuvant supplementation with selenium (Se) improves Se status and reduces the radiation-induced side-effects of patients treated by adjuvant radiotherapy (RT) for cervical and uterine cancer. Now, a potential relation between the planning target volume (PTV) of the RT and the Se effect concerning radiation induced diarrhoea was evaluated in detail., Methods: Whole blood Se concentrations had been measured in patients with cervical (n=11) and uterine cancer (n=70) after surgical treatment, during, and at the end of RT. Patients with initial Se concentrations of less than 84 μg/l were categorized as Se-deficient and randomized before RT to receive Se (as sodium selenite) per os on the days of RT, or to receive no supplement during RT. Diarrhoea was graded according to the Common Toxicity Criteria system (CTC, Version 2a). The evaluation of the PTV of the RT was ascertained with the help of a specialised computer-assisted treatment planning software used for radiation planning procedure., Results: A total of 81 patients had been randomized for the initial supplementation study, 39 of which received Se [selenium group, SeG] and 42 serving as controls [control group, CG]. Mean Se levels did not differ between SeG and CG upon study initiation, but were significantly higher in the SeG compared to the CG at the end of RT. The actuarial incidence of at least CTC 2 radiation induced diarrhoea in the SeG was 20.5% compared to 44.5% in the CG (p=0.04). The median PTV in both groups was 1302 ml (916-4608). With a PTV of <= 1302 ml (n=41) the actuarial incidence of at least CTC 2 diarrhoea in the SeG was 22.3% (4 of 18 patients) compared to 34.8% (8 of 23 patients) in the CG (p=0.50). In patients with a PTV of > 1302 ml (n=40) the actuarial incidence of at least CTC 2 diarrhoea in the SeG was 19.1% (4 of 21 patients) versus 52.6% (10 of 19 patients) in the CG (p=0.046)., Conclusions: Se supplementation during RT was effective to improve blood Se status in Se-deficient cervical and uterine cancer patients, and reduces episodes and severity of RT-induced diarrhoea. This effect was most pronounced and significant in patients with large PTV (> 1302 ml).

Introduction: Several studies have questioned the prognostic accuracy of the TNM system for oral cancer since neither patient's comorbidity, specific tumor related factors nor multimodal treatment regimens such as preoperative radiochemotherapy (RCT) are incorporated. The present study was performed in order to evaluate the prognostic impact of cTNM and ypTNM in oral cancer patients treated with preoperative RCT and resection., Methods: In this retrospective analysis a total of 139 patients (103 male, 36 female, average age 56.8 years) with oral squamous cell carcinoma (UICC II-IVb) were included. Treatment consisted of concomitant RCT with 39.6 Gy radiations and Carboplatin (cumulative dose 300 mg/m(2)) during the first week of radiation, as well as surgical tumor resection and neck dissection., Results: During the mean follow up of 88.9 months 86 patients (61.9%) died. Locoregional recurrences occurred in 41 patients (29.5%). The 5 years overall survival rate was 45.5%. In univariate analysis margin status, ypT, ypN and ypUICC as well as complete pathological response revealed statistical significance on overall survival. In multivariate analysis ypT, ypN and margin status showed independent prognostic impact in our cohort. Neither cT nor cN provided statistical association with overall survival., Conclusion: Results indicate that the clinical staging status of advanced oral cancer prior to preoperative RCT and resection should be interpreted with caution in terms of prognosis., (Copyright © 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: Radiotherapy constitutes an essential element in the multimodal therapy of Ewing's sarcoma. Compared to other sarcomas, Ewing tumors normally show a good response to radiotherapy. However, there are consistently tumors with a radioresistant phenotype, and the underlying mechanisms are not known in detail. Here we investigated the association between survivin protein expression and the radiosensitivity of Ewing's sarcoma in vitro., Material and Methods: An siRNA-based knockdown approach was used to investigate the influence of survivin expression on cell proliferation, double-strand break (DSB) induction and repair, apoptosis and colony-forming ability in four Ewing's sarcoma cell lines with and without irradiation., Results: Survivin protein and mRNA were upregulated in all cell lines tested in a dose-dependent manner. As a result of survivin knockdown, STA-ET-1 cells showed reduced cell proliferation, an increased number of radiation-induced DSBs, and reduced repair. Apoptosis was increased by knockdown alone and increased further in combination with irradiation. Colony formation was significantly reduced by survivin knockdown in combination with irradiation., Conclusion: Survivin is a radiation-inducible protein in Ewing's sarcoma and its down-regulation sensitizes cells toward irradiation. Survivin knockdown in combination with radiation inhibits cell proliferation, repair, and colony formation significantly and increases apoptosis more than each single treatment alone. This might open new perspectives in the radiation treatment of Ewing's sarcoma.

Background: To evaluate long-term toxicity and efficacy of a combined modality strategy including extended-field radiotherapy (EF-RT) or involved-field radiotherapy (IF-RT), the German Hodgkin Study Group carried out a follow-up analysis in patients with early unfavorable Hodgkin's lymphoma (HL)., Patients and Methods: One thousand two hundred and four patients were randomized to four cycles of chemotherapy followed by either 30 Gy EF- or 30 Gy IF-RT (HD8 trial); 532 patients in each treatment arm were eligible., Results: At 10 years, no arm differences were revealed with respect to freedom from treatment failure (FFTF) (79.8% versus 79.7%), progression-free survival (79.8% versus 80.0%), and overall survival (86.4% versus 87.3%). Non-inferiority of IF-RT was demonstrated for the primary end point FFTF (95% confidence interval for hazard ratio 0.72-1.25). Elderly patients had a poorer outcome when treated with EF-RT. So far, 15.0% of patients in arm A and 12.2% in arm B died, mostly due to secondary malignancies (5.3% versus 3.4%) or HL (3.2% versus 3.4%). After EF-RT, there were more secondary malignancies overall (58 versus 45), especially acute myeloid leukemias (11 versus 4)., Conclusion: Radiotherapy intensity reduction to IF-RT does not result in poorer long-term outcome but is associated with less acute toxicity and might be associated with less secondary malignancies.

Background: The aim of our study was to evaluate retrospectively whether neoadjuvant or adjuvant radiochemotherapy yields better survival for patients with N2-oral squamous cell carcinoma and to identify subgroups, which may benefit from one of the therapeutic settings. No studies have been carried out to investigate whether radiochemotherapy should be applied before or after surgery., Methods: In total, 151 patients with oral squamous cell carcinoma with N2-nodal-status were reviewed. Eighty five patients received neoadjuvant radiochemotherapy, 66 patients were treated with surgery and adjuvant radiochemotherapy. Overall survival was plotted by Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analysis., Results: Patients treated with neoadjuvant radiochemotherapy had a significantly improved 5-year survival in comparison to patients, who received adjuvant radiochemotherapy (46.3% vs. 27.4%, p=0.035). A subgroup analysis by T-stage revealed that neoadjuvant and adjuvant radiochemotherapy yielded similar 5-year survival rates for patients with T2N2-tumors (42.3% vs. 41.2%, p=0.871), whereas patients with T4bN2-tumors significantly benefitted from neoadjuvant treatment (37.3% vs. 9.7%, p=0.019)., Conclusions: Neoadjuvant radiochemotherapy is an effective treatment for patients with nodal status N2-oral squamous cell carcinoma, however prospective randomized trials are needed to confirm, which patients should be treated with neoadjuvant or adjuvant radiochemotherapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background and Purpose: Conventional algorithms show uncertainties in dose calculation already for three-dimensional conformal radiotherapy (3D-CRT). Intensity-modulated radiotherapy (IMRT) might even increase these. We wanted to assess differences in dose distribution for pencil beam (PB), collapsed cone (CC), and Monte Carlo (MC) algorithm for both 3D-CRT and IMRT in patients with mediastinal Hodgkin lymphoma., Patients and Methods: Based on 20 computed tomograph (CT) datasets of patients with mediastinal Hodgkin lymphoma, we created treatment plans according to the guidelines of the German Hodgkin Study Group (GHSG) with PB and CC algorithm for 3D-CRT and with PB and MC algorithm for IMRT. Doses were compared for planning target volume (PTV) and organs at risk., Results: For 3D-CRT, PB overestimated PTV(95) and V(20) of the lung by 6.9% and 3.3% and underestimated V(10) of the lung by 5.8%, compared to the CC algorithm. For IMRT, PB overestimated PTV(95), V(20) of the lung, V(25) of the heart and V(10) of the female left/right breast by 8.1%, 25.8%, 14.0% and 43.6%/189.1%, and underestimated V(10) of the lung, V(4) of the heart and V(4) of the female left/right breast by 6.3%, 6.8% and 23.2%/15.6%, compared to MC., Conclusion: The PB algorithm underestimates low doses to the organs at risk and overestimates dose to PTV and high doses to the organs at risk. For 3D-CRT, a well-modeled PB algorithm is clinically acceptable; for IMRT planning, however, an advanced algorithm such as CC or MC should be used at least for part of the plan optimization.

Background: The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy., Methods: In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041., Findings: Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy., Interpretation: Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting., Funding: Deutsche Krebshilfe and the Swiss Federal Government., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Giant cell tumor of the bone (GCTB) is a benign or sometimes semi-malignant neoplasm accounting for 5% of all primary bone tumors. This type of tumor has been historically considered as radioresistant, but nowadays radiotherapy (RT) is used in unresectable, recurrent or incompletely resected cases. Since the value of RT is not well defined, a national cohort study was conducted., Patients and Methods: Six German institutions collected data from 35 patients treated during the last 35 years and analyzed them., Results: From 1975-2010 16 male and 19 female patients with 39 lesions were irradiated for GCTB. The median age was 30 years and the median follow-up 65 months. Nineteen patients had undergone RT for recurrent or unresectable disease and 16 patients for non-in-sano resection. The actuarial 5-year overall and disease-free survival rates were 90% and 59%, respectively., Conclusion: RT is an easy, safe and effective method for the treatment of GCTB. It may provide an attractive alternative to mutilating surgery.

Purpose: Cure rates of early Hodgkin lymphoma (HL) are high, and avoidance of late complications and second malignancies have become increasingly important. This comparative treatment planning study analyzes to what extent target volume reduction to involved-node (IN) and intensity-modulated (IM) radiotherapy (RT), compared with involved-field (IF) and three-dimensional (3D) RT, can reduce doses to organs at risk (OAR)., Methods and Materials: Based on 20 computed tomography (CT) datasets of patients with early unfavorable mediastinal HL, we created treatment plans for 3D-RT and IMRT for both the IF and IN according to the guidelines of the German Hodgkin Study Group (GHSG). As OAR, we defined heart, lung, breasts, and spinal cord. Dose-volume histograms (DVHs) were evaluated for planning target volumes (PTVs) and OAR., Results: Average IF-PTV and IN-PTV were 1705 cm(3) and 1015 cm(3), respectively. Mean doses to the PTVs were almost identical for all plans. For IF-PTV/IN-PTV, conformity was better with IMRT and homogeneity was better with 3D-RT. Mean doses to the heart (17.94/9.19 Gy for 3D-RT and 13.76/7.42 Gy for IMRT) and spinal cord (23.93/13.78 Gy for 3D-RT and 19.16/11.55 Gy for IMRT) were reduced by IMRT, whereas mean doses to lung (10.62/8.57 Gy for 3D-RT and 12.77/9.64 Gy for IMRT) and breasts (left 4.37/3.42 Gy for 3D-RT and 6.04/4.59 Gy for IMRT, and right 2.30/1.63 Gy for 3D-RT and 5.37/3.53 Gy for IMRT) were increased. Volume exposed to high doses was smaller for IMRT, whereas volume exposed to low doses was smaller for 3D-RT. Pronounced benefits of IMRT were observed for patients with lymph nodes anterior to the heart. IN-RT achieved substantially better values than IF-RT for almost all OAR parameters, i.e., dose reduction of 20% to 50%, regardless of radiation technique., Conclusions: Reduction of target volume to IN most effectively improves OAR sparing, but is still considered investigational. For the time being, IMRT should be considered for large PTVs especially when the anterior mediastinum is involved., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In recent years, a special type of cancer cell--the cancer stem cell (CSC)--has been identified and characterized for different tumors. CSCs may be responsible for the recurrence of a tumor following a primarily successful therapy and are thought to bear a high metastatic potential. For the development of efficient treatment strategies, the establishment of reliable methods for the identification and effective isolation of CSCs is imperative. Similar to their stem cell counterparts in bone marrow or small intestine, different cluster of differentiation surface antigens have been characterized, thus enabling researchers to identify them within the tumor bulk and to determine their degree of differentiation. In addition, functional properties characteristic of stem cells can be measured. Side population analysis is based on the stem cell-specific activity of certain ATP-binding cassette transporter proteins, which are able to transport fluorescent dyes out of the cells. Furthermore, the stem cell-specific presence of aldehyde dehydrogenase isoform 1 can be used for CSC labeling. However, the flow cytometric analysis of these CSC functional features requires specific technical adjustments. This review focuses on the principles and strategies of the flow cytometric analysis of CSCs and provides an overview of current protocols as well as technical requirements and pitfalls. A special focus is set on side population analysis and analysis of ALDH activity. Flow cytometry-based sorting principles and future flow cytometric applications for CSC analysis are also discussed., (Copyright © 2012 International Society for Advancement of Cytometry.)

Radiotherapy is a powerful cure for several types of solid tumours, but its application is often limited because of severe side effects in individual patients. With the aim to find biomarkers capable of predicting normal tissue side reactions we analysed the radiation responses of cells from individual head and neck tumour and breast cancer patients of different clinical radiosensitivity in a multicentric study. Multiple parameters of cellular radiosensitivity were analysed in coded samples of peripheral blood lymphocytes (PBLs) and derived lymphoblastoid cell lines (LCLs) from 15 clinical radio-hypersensitive tumour patients and compared to age- and sex-matched non-radiosensitive patient controls and 15 lymphoblastoid cell lines from age- and sex- matched healthy controls of the KORA study. Experimental parameters included ionizing radiation (IR)-induced cell death (AnnexinV), induction and repair of DNA strand breaks (Comet assay), induction of yH2AX foci (as a result of DNA double strand breaks), and whole genome expression analyses. Considerable inter-individual differences in IR-induced DNA strand breaks and their repair and/or cell death could be detected in primary and immortalised cells with the applied assays. The group of clinically radiosensitive patients was not unequivocally distinguishable from normal responding patients nor were individual overreacting patients in the test system unambiguously identified by two different laboratories. Thus, the in vitro test systems investigated here seem not to be appropriate for a general prediction of clinical reactions during or after radiotherapy due to the experimental variability compared to the small effect of radiation sensitivity. Genome-wide expression analysis however revealed a set of 67 marker genes which were differentially induced 6 h after in vitro-irradiation in lymphocytes from radio-hypersensitive and non-radiosensitive patients. These results warrant future validation in larger cohorts in order to determine parameters potentially predictive for clinical radiosensitivity.

Background. The aim of our study was to evaluate the effects of neoadjuvant platinum-based radiochemotherapy (RCT) in patients with maxillary sinus squamous cell carcinoma and to compare the results with other multimodality treatment concepts for advanced-stage maxillary sinus carcinoma in the literature. Methods. In total, 53 patients with squamous cell carcinoma of the maxillary sinus were reviewed retrospectively. All patients received a neoadjuvant RCT containing either cisplatin or carboplatin followed by radical surgery. Overall survival and locoregional control were plotted by Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analysis. Results. Five-year overall survival for all patients was 35%. Eleven patients achieved a complete response after radiochemotherapy. The complete response rate was significantly higher for patients treated with cisplatin (P = 0.028); however the 5-year overall survival rates did not differ significantly (P = 0.673) for patients treated with cisplatin (37%) and carboplatin (32%). Orbital invasion (P = 0.005) and complete response to radiochemotherapy (P = 0.021) had a significant impact on overall survival in univariate analysis. Conclusions. Neoadjuvant radiochemotherapy followed by radical surgery is an effective treatment for patients with advanced maxillary sinus squamous cell carcinoma. In terms of treatment response cisplatin seems to be more effective than carboplatin.

The prognostic value of positron emission tomography (PET) in early therapy response assessment, after completion of chemotherapy and 3 months after the end of treatment in advanced Hodgkin lymphoma (HL) remains to be defined. We report the results of 69 patients with first presentation of advanced HL. [18F]-fluoro-2-deoxy-d-glucose (FDG)-PET scan was performed after four cycles (PET-4), on completion of chemotherapy after 6/8 cycles (PET-6/8) and 3 months after the completion of chemotherapy (PET 3-months). Median follow-up was 55 months. The negative predictive value (NPV) for PET-4, PET-6/8 and PET 3-months was 98%, 95% and 97%, respectively. The 4-year progression-free survival (PFS) for PET-4 negative (n = 51) and PET-4 positive (n = 18) patients was 96% and 78%, respectively (p = 0.016). The 4-year PFS for PET-6/8 negative (n = 59) and PET-6/8 positive (n = 9) patients was 95% and 78%, respectively (p = 0.046). Patients with a large mediastinal mass constituted nearly all of the PET-4 positive (16/18) and PET-6/8 positive (8/9) patients. After radiotherapy of PET-6/8 positive patients, PET 3-months was negative in 64 (97%) and positive in two (3%) patients. PET 3-months after the end of chemotherapy was of limited value when the interim PET-4 was negative. Interim PET after four cycles of bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP) is a strong prognostic marker for PFS in advanced HL.

Approximately 20% of all Hodgkin lymphoma (HL) patients are older than 60 years and have a poor prognosis, mainly because of increased treatment-related toxicity resulting in reduced overall dose intensity and more treatment-related mortality. To possibly improve the treatment of elderly HL patients, the German Hodgkin Study Group developed a new regimen, PVAG (prednisone, vinblastine, doxorubicin, and gemcitabine). In this multicenter phase 2 study, elderly HL patients in early unfavorable and advanced stages received 6 to 8 cycles of PVAG and additional radiotherapy if they were not in complete remission (CR) after chemotherapy. Endpoints included feasibility, acute toxicity, and response rate. Fifty-nine patients 60 to 75 years of age (median, 68 years) were eligible for analysis; 93% had advanced stage disease. WHO grade 3/4 toxicities were documented in 43 patients; 46 patients responded with CR/CR uncertain (78%). Within 37 months median observation time, 15 progressions or relapses and 17 deaths were observed, of which 8 were related to HL and 1 was the result of treatment-related toxicity. The 3-year estimates for overall survival and progression-free survival were 66% (95% CI, 50%-78%) and 58% (95% CI, 43%-71%), respectively. We conclude that PVAG is safe and feasible in elderly HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00147875.

Background: The purpose of this study was to evaluate the prognostic significance of different TNM-based stage groupings proposed in the literature., Methods: We conducted a retrospective analysis of 300 patients with primary oral squamous cell carcinoma (T1-4, N0-2, M0). The stage grouping systems of the sixth edition of the Union Internationale Contre le Cancer (UICC), T and N Integer Score (TANIS), the Snyderman scheme, the Hart scheme, and the Berg scheme were tested for their prognostic significance. Disease free survival (DFS) was plotted by Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analysis., Results: On univariate analysis, all systems revealed discriminatory power for DFS; however, on multivariate analysis, only the Hart scheme predicted DFS. The TANIS did not have a better prognostic ability than the UICC stage grouping., Conclusion: Unlike in previous studies, the UICC stage grouping did perform worse than other TNM-based stage groupings, which may be due to the alterations made in the sixth edition., (Copyright © 2010 Wiley Periodicals, Inc.)

Background: The efficacy of adjuvant radiochemotherapy (RCT) in patients with advanced stage head and neck carcinoma has been proven in prospective randomized trials. However, these trials focused on different head and neck sites. Specific analyses for treatment effects in squamous cell carcinoma of the oral cavity (OSCC) are missing. We evaluated our experiences with adjuvant concomitant RCT in advanced OSCC to compare the results with other treatment schemes using adjuvant RCT., Patients and Methods: A total of 183 patients with OSCC of UICC stages II-IVb were reviewed retrospectively. All patients were treated with radical surgery followed by adjuvant, conventional fractionated concomitant RCT using carboplatin. Overall survival was plotted by Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analysis., Results: Univariate analysis showed a significant impact of T, N, and UICC stage, histopathologic grading, surgical margins, extracaspular spread (ECS), and lymphangiosis carcinomatosa on overall survival (Table 3). Patients with stage IVa had a higher 5-year overall survival rate (42.8%) than patients with stage IVb (25.0%) (Figure 1). The differences were significant in multivariate analysis (p = 0.033) (Table 4)., Conclusion: Adjuvant concomitant RCT is an effective treatment in patients with advanced stage OSCC. However, it remains unclear, which patients should be treated with adjuvant RCT. For patients with stage IVb, adjuvant RCT yields poor results. Prospective randomized trials are needed to confirm which patients should be treated with adjuvant RCT.

Despite new therapeutic approaches patients with advanced oral squamous cell carcinoma still have a dismal prognosis. The main factor contributing to this problem is locoregional failure due to a lack of response to treatment. Several trials have proven the effect of neoadjuvant radiochemotherapy followed by radical surgery in comparison to primary surgery followed by adjuvant radiochemotherapy. No reliable parameters have been identified so far to predict response to radiochemotherapy. The aim of our study was to assess whether podoplanin expression in pretreatment biopsies could serve as a biomarker to predict the host response to neoadjuvant radiochemotherapy. In this retrospective study, podoplanin expression was examined in a set of 63 patients with oral squamous cell carcinoma by immunohistochemistry. We analyzed associations between the level of podoplanin expression and various clinicopathologic parameters, including response to radiochemotherapy, clinical and histological N-status. Furthermore we evaluated the effects of these parameters on overall survival and on locoregional control in univariate and multivariate analysis. The χ(2)-test revealed that high expression of podoplanin in pretreatment biopsy material was associated with non-regression of the tumor (p=0.013) and poor overall survival (p<0.001). Five-year survival rates of 92.9% for patients with weak expression and 15.0% for high expression were revealed. Podoplanin expression was also significantly associated with ypN status (p=0.004) and ypUICC status (p<0.001). We concluded that podoplanin might serve as a factor to predict treatment response in oral squamous cell carcinoma treated with neoadjuvant platin-based radiochemotherapy as well as a prognostic factor for overall survival and locoregional control., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Since its beginning, more than 16,000 patients have been enrolled in the multicentric randomized trials of the German Hodgkin Study Group (GHSG) for adult patients. Within 6 study generations, the treatment of Hodgkin lymphoma has been developed stepwise by using the results of the completed protocols. Now the sixth generation is active. According to the role of radiotherapy, the study group successfully evaluated different dose-effect relationships and could also prove the efficacy of involved-field radiotherapy in early stages in combination with effective chemotherapy. Currently, a radiation dose of 20 Gy to the involved field after a mildly aggressive chemotherapy (2 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine [ABVD]) should be the standard for early-favorable stages according to the GHSG classification. In early-unfavorable or intermediate-risk stages, involved-field radiation therapy with 30 Gy is sufficient; the optimal chemotherapy has to be fixed. For the advanced stages, the question of radiotherapy is still unclear. Preliminary results of the GHSG and others show that additive radiotherapy after intensive chemotherapy might be useful for elective subgroups of patients. The extensive radiotherapy quality assurance program, performed by the GHSG and its radiotherapy reference center, has proven to be successful and necessary to ensure that, with reduced radiation doses and reduced radiation volumes, precise radiotherapy, as defined by the protocol, will be performed by the participating radiotherapy departments.

Purpose: Since the 20(th) century, radiotherapy (RT) has been used for treatment of symptomatic splenomegaly (SM). SM occurs in association with hematologic disorders. The purpose of this analysis was to determine the indication, treatment concepts, and efficiency of RT., Material and Methods: Clinical features, treatment concepts, and outcome data during the past 20 years were analyzed. Endpoints were pain relief, symptomatic and hematological response, and treatment-related side effects., Results: From 1989-2009, a total of 122 patients received 246 RT courses because of symptomatic SM. Overall 31 patients had chronic myelogenous leukemia (CML), 37 had chronic lymphocytic leukemia (CLL), 23 had osteomyelofibrosis (OMF), 17 had polycythemia vera (PV), 5 had acute myelogenous leukemia, 4 had idiopathic thrombocytopenic purpura (ITP), 3 had non-Hodgkin lymphoma (NHL), and 2 had multiple myeloma (MM). Patients were treated with (60)Co gamma rays or 5-15MV photons. The fraction size ranged from 10-200 cGy and the total dose per treatment course from 30-1600 cGy. Significant pain relief was achieved for 74.8% of the RT courses given for splenic pain. At least 50% regression was attained for 77% of the RT courses given for SM. 36 patients died within 2 months due to the terminal nature of their disease. Of the RT courses applied for cytopenia, 73.6% achieved a significant improvement of hematological parameters and reduction of transfusion need. Notable hematologic toxicities were reported < EORTC/RTOG II°., Conclusion: The present analysis documents the efficacy of RT. In addition, RT as a palliative treatment option for symptomatic SM should not be forgotten.

Purpose: Preoperative radiochemotherapy is widely used in the treatment of locally advanced rectal cancer. The predictive value of response to neoadjuvant treatment remains uncertain. We retrospectively evaluated the impact of downstaging and tumor regression as prognostic factors and its influence on the ability to perform sphincter-sparing surgery., Patients and Methods: A total of 72 consecutive patients with advanced rectal cancer were included in this retrospective analysis. All patients were treated with preoperative 5-fluorouracil-based chemotherapy and pelvic radiation with a total dose of 50.4 Gy followed by surgery 6 weeks later., Results: A sphincter-preserving procedure could be performed on 42 patients, and in all 72 patients complete resection (R0) was achieved. A pathological complete response (ypT0, ypN0) was achieved in 8 (11%) patients. None of the patients showing a complete pathological response relapsed or died during the follow-up period. At a median follow-up of 28 months, 65 patients were alive, none of these patients had local recurrence and 15 patients had metastatic disease. Patients showing a complete pathological response had a significantly better 2-year disease-free survival compared to patients with ≥10% residual tumor cells (p = 0.024). Patients < 65 years showed a significantly better response rate, compared with those > 65 years of age (p = 0.036). Acute toxicity was moderate., Conclusion: Preoperative radiochemotherapy is an effective and safe treatment for patients with locally advanced rectal cancer. Pathological parameters after preoperative radiochemotherapy, including tumor regression grading, could be correlated with disease-free survival. The impact of tumor regression grading needs to be further validated in prospective clinical trials.

Background: The rising life expectancy of cancer patients has led to a greater need for treatment of spinal metastases. Interdisciplinary collaboration is important so that each patient's treatment can be properly tailored to the overall prognosis. The main factors to be considered are the histology of the primary tumor, potential spinal instability, and compression of neural structures., Methods: We discuss the treatment options for spinal metastases on the basis of a selective literature review and our own extensive experience in an interdisciplinary tumor center., Results: For spinal canal compression or impending spinal instability, the treatment of choice is decompression and stabilization, by either a dorsal approach (lumbar and thoracic spine) or a ventral approach (cervical spine). Radical ventral tumor resection is indicated only for solitary metastases in patients with a favorable long-range prognosis. If the tumor is radiosensitive, radiotherapy is given either as adjuvant treatment after surgery or as the primary treatment for multiple spinal metastases in the absence of an acute neurological deficit. Various fractionation schemes with different total radiation doses are used. Bisphosphonate treatment is an integral component of the overall treatment strategy., Conclusion: The treatment of spinal metastases requires interdisciplinary collaboration and must be tailored to each patient's overall prognosis.

Background: Carcinoma of the oral cavity is classified according to the TNM staging system of the UICC. The staging system is under continuous revision. The aim of our study was to assess the prognostic value of the UICC sixth edition for oral cancer, which was established in 2003., Methods: Three-hundred treatment-naive patients with oral squamous cell carcinoma (OSCC) of stages I-IVb were reviewed retrospectively. Patients with stage-I disease were treated solely surgically, and patients with stage II-IVb received a multimodal treatment. Overall survival was plotted by Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analysis., Results: Univariate analysis showed a significant impact of T stage (P = 0.009), N stage (P < 0.001), and UICC stage (P < 0.001) on overall survival. However, no statistical differences were observed between stages T4a and T4b (P = 0.176) and UICC stages IVa and IVb (P = 0.306)., Conclusions: T stage, N stage, and UICC stage grouping are good predictors of overall survival in patients with OSCC. Neither the division of stage T4 into T4a and T4b in the sixth edition nor the split of stage IV into IVa and IVb showed significant differences in overall survival between the subgroups., (J. Surg. Oncol. 2010;102:443-449. © 2010 Wiley-Liss, Inc.)