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Treatment of localized cancer with protons therapy (PT) seems an appealing alternative to photons. PT has been available for decades and has unique dose distribution properties with the so-called Bragg-peak enabling protons to stop after their maximum depth is reached within millimeters. PT allows sparing of normal tissues and organs to a much greater extent than photons, even when modern photon techniques like intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) are involved. Whereas IMRT and VMAT techniques have demonstrated their superiority to older 3D-conformal irradiation techniques, there is still a large gap between the theoretical advantages of PT due to its superior dose distribution and high-level clinical evidence, particularly in head and neck cancer (HNC). So far, mostly non-randomized clinical studies exist with clinical results in oropharyngeal, nasopharyngeal, sinonasal, periorbital, and salivary gland cancer. The limited broad availability of this treatment method and its unknown cost-effectiveness need to be evaluated. In this chapter, we discuss the currently available evidence of PT for HNCs and viable options to generate further evidence like the model-based approach.

Background Salvage radiotherapy (SRT) is utilized for biochemical progression of prostate cancer after radical prostatectomy (RP). Objective To report the outcomes of the SAKK 09/10 trial comparing conventional and dose-intensified SRT. Design, setting, and participants SAKK 09/10 was a randomized, multicenter, phase 3 trial that recruited men with biochemical progression after RP. Intervention Patients were randomly assigned to conventional-dose (64 Gy) or dose-intensified SRT (70 Gy) to the prostate bed without hormonal therapy. Outcome measurements and statistical analysis The primary endpoint was freedom from biochemical progression (FFBP). Secondary endpoints included clinical progression-free survival (PFS), time to hormonal treatment, overall survival (OS), acute and late toxicity (Common Terminology Criteria for Adverse Events v4.0), and quality of life (QoL). Results and limitations Between February 2011 and April 2014, 350 patients were randomly assigned to 64 Gy (n = 175) or 70 Gy (n = 175). Median prostate-specific antigen at randomization was 0.3 ng/ml. After median follow-up of 6.2 yr, the median FFBP was 8.2 yr in the 64 Gy arm and 7.6 in the 70 Gy arm (log-rank p = 0.4), with a hazard ratio of 1.14 (95% confidence interval 0.82–1.60). The 6-year FFBP rates were 62% and 61%, respectively. No significant differences in clinical PFS, time to hormonal treatment, or OS were observed. Late grade 2 and 3 genitourinary toxicity was observed in 35 (21%) and 13 (7.9%) patients in the 64 Gy arm, and 46 (26%) and seven (4%) in the 70 Gy arm, respectively (p = 0.8). Late grade 2 and 3 gastrointestinal toxicity was observed in 12 (7.3%) and seven patients (4.2%) in the 64 Gy arm, and 35 (20%) and four (2.3%) in the 70 Gy arm, respectively (p = 0.009). There were no significant differences in QoL. Conclusions Conventional-dose SRT to the prostate bed is sufficient in patients with early biochemical progression of prostate cancer after RP. Patient summary The optimal radiation therapy dose for patients who have increased tumor markers after surgery for prostate cancer is unclear. We found that administering a higher dose only increased the gastrointestinal side effects without providing any benefits to the patient. This clinical trial is registered on ClinicalTrials.gov as NCT01272050.

Prognosis after chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC) shows marked differences among patients according to TNM subgroups, however individualized risk assessment tools to better stratify patients for treatment (de-) escalation or intensified follow-up are lacking in ASCC.Patients' data from eight sites of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG), comprising a total of 605 patients with ASCC, treated with standard definitive CRT with 5-FU/Mitomycin C or Capecitabine/Mitomycin C between 2004-2018, were used to evaluate prognostic factors based on Cox regression models for disease-free survival (DFS). Evaluated variables included age, gender, Karnofsky performance score (KPS), HIV-status, T-category, lymph node status and laboratory parameters. Multivariate cox models were separately constructed for the whole cohort and the subset of patients with early-stage (cT1-2 N0M0) tumors.After a median follow-up of 46 months, 3-year DFS for patients with early-stage ASCC was 84.9%, and 67.1% for patients with locally-advanced disease (HR 2.4, p 0.001). T-category (HR vs. T1: T2 2.02; T3 2.11; T4 3.03), N-category (HR versus N0: 1.8 for N1-3), age (HR 1.02 per year), and KPS (HR 0.8 per step) were significant predictors for DFS in multivariate analysis in the entire cohort. The model performed with a C-index of 0.68. In cT1-2N0 patients, T-category (HR 2.14), HIV status (HR 2.57), age (1.026 per year), KPS (HR 0.7 per step) and elevated platelets (HR 1.3 per 100/nl) were associated with worse DFS (C-index of 0.7).Classical clinicopathologic parameters like T-category, N-category, age and KPS remain to be significant prognostic factors for DFS in patients treated with contemporary CRT for ASCC. HIV and platelets were significantly associated with worse DFS in patients with early stage ASCC.

Contains fulltext : 235407.pdf (Publisher’s version ) (Closed access) BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRT(P)) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRT(P) (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC(TaxPF)-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and IC(TaxPF) followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or IC(TaxPF)-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

A number of national and international societies published recommendations regarding the required equipment and manpower assumed to be necessary to treat a number of patients with radiotherapy. None of these recommendations were based on actual time measurements needed for specific radiotherapy procedures. The German Society of Radiation Oncology (DEGRO) was interested in substantiating these recommendations by prospective evaluations of all important core procedures of radiotherapy in the most frequent cancers treated by radiotherapy. The results of the examinations of radiotherapy with intensity-modulated radiation therapy (IMRT) in patients with different tumor entities are presented in this manuscript. Four radiation therapy centers [University Hospital of Marburg, University Hospital of Giessen, University Hospital of Berlin (Charite), Klinikum rechts der Isar der Technischen Universitat Munchen] participated in this prospective study. The workload of the different occupational groups and room occupancies for the core procedures of radiotherapy were prospectively documented during a 2-month period per center and subsequently statistically analyzed. The time needed per patient varied considerably between individual patients and between centers for all the evaluated procedures. The technical preparation (contouring of target volume and organs at risk, treatment planning, and approval of treatment plan) was the most time-consuming process taking 3 h 54 min on average. The time taken by the medical physicists for this procedure amounted to about 57 %. The training part of the preparation time was 87 % of the measured time for the senior physician and resident. The total workload for all involved personnel comprised 74.9 min of manpower for the first treatment, 39.7 min for a routine treatment with image guidance, and 22.8 min without image guidance. The mean room occupancy varied between 10.6 min (routine treatment without image guidance) and 23.7 min (first treatment with image guidance). The prospective data presented here allow for an estimate of the required machine time and manpower needed for the core procedures of radiotherapy in an average radiation treatment with IMRT. However, one should be aware that a number of necessary and time-consuming activities were not evaluated in the present study.

Despite recent advances in radiochemotherapy, treatment of locally advanced head and neck squamous cell carcinoma is still challenging, and survival rates have improved only slightly. This is due to the high frequency of metastases and local and/or regional tumor recurrences that have acquired radio- or chemoresistance. MiRNAs regulate diverse processes in tumorigenesis, metastasis, and therapy resistance in head and neck squamous cell carcinoma. Hence, miRNAs are highly valued in biomarker studies. Establishment of the miRNA profiles of oropharyngeal tumors enables personalized treatment selection, since expression of distinct miRNAs can predict the response to two different radiochemotherapy regimens. Development of novel miRNA therapeutics has a high clinical potential for further improving treatment of cancerous disease. The use of nanoparticles with distinct surface modifications as miRNA vectors permits prolonged bioavailability, high efficacy in tumor targeting, and low toxicity. Nevertheless, the efficacy of miRNA therapy has only been shown in animal models to date.

Primary malignant bone neoplasms are relatively rare. The most common bone tumors are osteosarcoma,Ewing's sarcoma,chondrosarcoma, fibrosarcoma,malignant fibrous histiocytoma of bone, giant cell tumor, aneurysmal bone cyst and chordoma. These tumors are generally considered to be a radioresistant entities, but it has been suggested that radiotherapy may be effective in a palliative and in some curative situations, if a sufficient dose is given to an adequate volume. Only for the management of primary Ewing's sarcoma the radiation therapy is an essential part in the multimodal therapy concept. The most common bone neoplasms and the role of the radiotherapy are discussed in these chapter.

The European Organisation for Research and Treatment of Cancer (EORTC) Radiotherapy (RT) Group will celebrate 27 years of activity in 2002. During its long history, the Radiotherapy Group has conducted a large number of studies which have provided valuable information on the radiation treatment of several disease sites. Group efforts have been concentrated on dose-effect studies, optimal fractionation schemes, combinations with other treatment modalities, and new radiotherapy techniques. The EORTC RT Group was the first in Europe to develop and introduce methodologies of Quality Assurance in radiotherapy. The RT Group actively collaborates with other EORTC Groups and international organisations. Currently, several phase III studies are being conducted in collaboration with European, North American and Australian organisations. The collaboration with RTOG led to the setting up of common systems for scoring late normal tissue effects. In the years to come, the Group will keep pioneering pivotal trials in radiotherapy and radio-chemotherapy. It will also explore combinations with novel therapies in phase I trials and implement innovative translational research programmes.

History and clinical findings A 40-year-old man was admitted with acute onset of positional vertigo, nausea and vomiting. Neurological examination revealed a fatigable nystagmus to the upward ear in positional testing, to the right more than to the left, as well as latent paresis and rigidity of the left arm. Investigations Magnetic resonance imaging of the brain revealed two space-occupying lesions in the cerebellum and pons. Open biopsy showed a highly malignant B-cell lymphoma of Burkitt type. There was no evidence of acquired or congenital immunodeficiency. As there were no significant abnormalities outside of the CNS, a primary lymphoma in this location was diagnosed. Treatment and course Chemotherapy with a combination of drugs including methotrexate achieved only partial remission. Subsequent radiotherapy brought about full remission, which has now lasted for over a year. Conclusions Treatment of first choice of a primary cerebral lymphoma in an immunocompetent patient is chemotherapy with cerebrospinal fluid-permeable cytostatics. Partial remission should be followed by radiotherapy.

In this retrospective study, 162 breast cancer patients were analysed in whom brain metastases had been diagnosed clinically between 1969 and 1995 at a single institution. 145 patients were treated with megavoltage irradiation (60 cobalt or 6MV) of the whole brain using opposed fields. The most common applied schedule consisted of 30 Gy in 15 daily fractions over 3 weeks. 10 patients underwent surgery and 17 patients received symptomatic treatment only. The median age was 50 years (range 30-78 years). 81 of 162 patients (50%) were premenopausal. Women younger than 40 years of age had a shorter survival (median 12 weeks) than those of all other groups (median 29 weeks). Median survival was 82 weeks for the 10 surgical patients, 26 weeks for the 145 patients treated with radiotherapy and 5 weeks for the patients who received symptomatic (corticosteroid) therapy only. Patients with solitary metastases treated with radiation alone (45 patients) had a survival of 44 weeks versus 23 weeks in patients with multiple brain metastases. Multivariate stepwise regression analyses revealed Karnofsky Index, dose of radiation (P0.001), solitary metastases (P0.04) and primary tumour size (P0.04) as significant prognostic factors for survival.

Definitive chemoradiation is a well-established option in the treatment of locally advanced squamous cell carcinoma of the head and neck. The intention of this study was to evaluate its efficacy on cervical lymph node metastases in a prospective study after a standardized protocol for chemoradiation (CRT) and histopathological evaluation, respectively.The data of 25 patients (10 oropharynx, 15 hypopharynx) who received planned neck dissection after definitive chemoradiation for UICC stage IV carcinomas of the pharynx were analyzed. All patients were sonomorphologically staged positive for lymph nodes (3 patients: N1; 2 patients N2a; 7 patients N2b; 9 patients N2c and 4 patients N3). A neck dissection was carried out 8.9+/-1.5 weeks (range 6-13) post treatment. The specimens obtained from the different neck levels were histologically examined for viable tumour cells.Local control was achieved in 100% of all patients on endoscopy 9 weeks after the chemoradiation. In 14/25 patients (56%), still viable tumour tissue was found in the neck dissection (ND) specimen. Only one of these 14 patients (7%) was deemed suspicious for residual lymphadenopathy from clinical and diagnostic findings at re-staging after chemoradiation, the others were staged yN0. Postsurgical complications occurred in six patients (24%) such as bleeding and prolonged wound healing in one patient each and functional deficits in an additional four patients. One patient developed a scar recurrence seven months after surgery.Based on these findings, the ultimate efficacy of primary CRT should not be judged 8-10 weeks after the treatment. Therefore planned neck dissection should be performed no earlier than 12 weeks after primary CRT.

There is an increasing body of evidence showing that patients with resectable pancreatic cancer might benefit from adjuvant therapy. Based on phase III trials, potential options for adjuvant treatment are chemotherapy alone or a multimodal approach involving radiotherapy. Available data are heterogeneous and have been discussed controversially. Hitherto, a worldwide standard of care has not yet been established. Adequate patient selection might be the key element for a tailored adjuvant treatment. Clinical research currently focusses on gemcitabine alone or in combination, and some molecular biologic approaches with epidermal growth factor receptor monoclonal antibodies (EGFR-MoABs) and anti-angiogenic drugs. Recent advances in radiooncology offer better dose conformality and reduced morbidities. Currently, the co-operative Radiotherapy and Gastrointestinal Groups have launched a multicentric European Organization for Research and Treatment of Cancer (EORTC) trial investigating the impact of radiotherapy in combination with gemcitabine in R0-resected pancreatic head cancer.

A systematic comparison of three-dimensional MR (magnetic resonance) thermography and planning calculations in phantoms for the hyperthermia (HT) SIGMA-Eye applicator. We performed 2 x 6 experiments in a homogeneous cylindrical and a heterogeneous elliptical phantom by adjusting 82 different patterns with different phase control inside an MR tomograph (Siemens Magnetom Symphony, 1.5 Tesla). For MR thermography, we employed the proton resonance frequency shift method with a drift correction based on silicon tubes. For the planning calculations, we used the finite-difference time-domain (FDTD) method and, in addition, modeled the antennas and the transforming network. We generated regions according to a segmentation of bones and tissue, and used an interpolation technique with a subgrid of 0.5 cm size at the interfaces. A Gauss-Newton solver has been developed to adapt phases and amplitudes. A qualitative agreement between the planning program and measurements was obtained, including a correct prediction of hot spot locations. The final deviation between planning and measurement is in the range of 2-3 W/kg, i.e., below 10%. Additional HT phase and amplitude adaptation, as well as position correction of the phantom in the SIGMA-Eye, further improve the results. HT phase corrections in the range of 30-40 degrees and HT amplitude corrections of +/- 20-30% are required for the best agreement. The deviation /MR-FDTD/, and the HT phase/amplitude corrections depend on the type of phantom, certain channel groups, pattern steering, and the positioning error. Appropriate agreement between three-dimensional specific absorption rate distributions measured by MR-thermography and planning calculations is achieved, if the correct position and adapted feed point parameters are considered. As long as feed-point parameters are uncertain (i.e., cannot be directly measured during therapy), a prospective planning will remain difficult. However, we can use the information of MR thermography to better predict the patterns in the future even without the knowledge of feed-point parameters.

Die Kombination von Chemo- und Strahlentherapie hat in den letzten Jahren in multimodalen Protokollen erheblich an Bedeutung gewonnen. Die verschiedenen Interaktionsmoglichkeiten sind komplex. Aus strahlenbiologischer Sicht mussen zwei grundsatzlich verschiedene Konzepte voneinander differenziert werden, namlich das Prinzip der raumlichen Kooperation (beide Modalitaten wirken unabhangig voneinander an verschiedenen Zielorten, also lokal bzw. systemisch) und das Konzept der lokalen Wirkungsverstarkung (Radiosensibilisierung). Diese Unterscheidung ist konzeptionell notig, um die optimale Auswahl der Medikamente und Dosierungen sowie die zeitliche Abfolge von Bestrahlung und Chemotherapie festzulegen.

Primary malignant bone neoplasms are relatively rare. The most common bone tumors are osteosarcoma,Ewing's sarcoma,chondrosarcoma, fibrosarcoma,malignant fibrous histiocytoma of bone, giant cell tumor, aneurysmal bone cyst and chordoma. These tumors are generally considered to be a radioresistant entities, but it has been suggested that radiotherapy may be effective in a palliative and in some curative situations, if a sufficient dose is given to an adequate volume. Only for the management of primary Ewing's sarcoma the radiation therapy is an essential part in the multimodal therapy concept. The most common bone neoplasms and the role of the radiotherapy are discussed in these chapter.

The European Organisation for Research and Treatment of Cancer (EORTC) Radiotherapy (RT) Group will celebrate 27 years of activity in 2002. During its long history, the Radiotherapy Group has conducted a large number of studies which have provided valuable information on the radiation treatment of several disease sites. Group efforts have been concentrated on dose-effect studies, optimal fractionation schemes, combinations with other treatment modalities, and new radiotherapy techniques. The EORTC RT Group was the first in Europe to develop and introduce methodologies of Quality Assurance in radiotherapy. The RT Group actively collaborates with other EORTC Groups and international organisations. Currently, several phase III studies are being conducted in collaboration with European, North American and Australian organisations. The collaboration with RTOG led to the setting up of common systems for scoring late normal tissue effects. In the years to come, the Group will keep pioneering pivotal trials in radiotherapy and radio-chemotherapy. It will also explore combinations with novel therapies in phase I trials and implement innovative translational research programmes.

This study investigates whether similarly named subscales of three quality of life questionnaires, the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30), the Medical Outcome Study Quality of Life Questionnaire Short Form 36 (SF-36) and the Functional Living Index Cancer questionnaire (FLIC) assess similar aspects of the patients' quality of life. A multitrait multimethod analysis on the answers of 234 cancer patients showed that subscale correlations as indicators of convergent validity significantly exceed corresponding correlations of discriminant validity in five of the seven dimensions analysed (physical functioning, emotional functioning, pain, fatigue/vitality and nausea/vomiting). The results of the social functioning and overall health subscales are less clear. Content analysis of the social functioning scales reveals that this domain is differently operationalised in the three questionnaires. Linear regressions of the overall health subscales suggest that patients interpret overall health questions of the three questionnaires differently. The results show that overall health subscales of these three questionnaires cannot be equated, while most specific subscales provide valid results.