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Raising plasma free fatty acid (FFA) levels reduces muscle glucose uptake, but the effect of FFAs on splanchnic glucose uptake, total glucose output, and glucose cycling may also be critical to producing lipid-induced glucose intolerance. In eight normal volunteers, we measured glucose turnover and cycling rates ([2H7]glucose infusion) during a moderately hyperglycemic (7.7 mmol/l) hyperinsulinemic clamp, before and after ingestion of a labeled (dideuterated) oral glucose load (700 mg/kg). Each test was performed twice, with either a lipid or a saline infusion; four subjects also had a third test with a glycerol infusion. As shown by similar rates of exogenous glucose appearance, the lipid infusion did not reduce first-pass splanchnic glucose uptake (saline 1.48+/-0.18, lipid 1.69+/-0.17, and glycerol 1.88+/-0.17 mmol/kg per 180 min; NS), but it reduced peripheral glucose uptake by 40% (P < 0.01 vs. both saline and glycerol infusions). Before oral ingestion of glucose, total glucose output was similarly increased by the lipid and glycerol infusions. Total glucose output was significantly increased by FFAs after oral ingestion of glucose (saline 3.68+/-1.15, glycerol 3.68+/-1.70, and lipid 7.92+/-0.88 micromol x kg(-1) x min(-1); P < 0.01 vs. saline and P < 0.05 vs. glycerol). The glucose cycling rate was approximately 2.7 micromol x kg(-1) x min(-1) with the three infusions and tended to decrease all along the lipid infusion, which argues against a stimulation of glucose-6-phosphatase by FFAs. It is concluded that in situations of moderate hyperinsulinemia-hyperglycemia, FFAs reduce peripheral but not splanchnic glucose uptake. Total glucose output is increased by FFAs, by a mechanism that does not seem to involve stimulation of glucose-6-phosphatase. [ABSTRACT FROM AUTHOR]

Rectal cancer typically necessitates a combination of radiotherapy (RT), chemotherapy, and surgery. The associated functional disorders and reduction in quality of life have led to an increasing interest in organ preservation strategies. Response strongly correlates with RT dose, but dose escalation with external beam remains limited even with modern external beam RT techniques because of toxicity of the surrounding tissues. This study reports on the use of Papillon, an endocavitary Radiotherapy device, in the treatment of rectal cancer. The device delivers low energy X-rays, allowing for safe dose escalation and better complete response rate. Between January 2015 and February 2024, 24 rectal cancer patients were treated with the addition of a boost delivered by Papillon to standard RT, with or without chemotherapy, in an upfront organ preservation strategy. After a median follow-up (FU) of 43 months, the organ preservation rate was 96% (23/24), and the local relapse rate was 8% (2/24). None of our patients developed grade 3 or more toxicities. Our results demonstrate that the addition of Papillon contact RT provides a high rate of local remission with sustained long-term organ preservation, offering a promising alternative to traditional surgical approaches in patients with rectal cancer.

The European SocieTy for Radiation and Oncology -Advisory Committee on Radiation Oncology Practice (ESTRO-ACROP) endorsed a project to provide guidelines (GL) for the identification and delineation of clinically negative lymph-nodal stations (LNs) involved in upper gastrointestinal clinical scenarios. The presented GL is focused on preoperative (or definitive) setting. The project aim is to improve the consistency of clinical target volume (CTV) delineation by providing: a description of the anatomical boundaries of the LNs; a radiological computed tomography-based atlas depicting the LNs areas; a free, web-based, interactive example case for independent training of radiation oncologists on LNs delineation according to the presented GL, by both qualitative and quantitative analysis (through the FALCON EduCase platform). This project was carried out with the intention to facilitate and improve uniformity of future upper gastrointestinal guidelines on nodal CTV delineation. We report methodology and results from the collaboration of a working group panel selected by the ESTRO-ACROP., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: Concomitant external-beam radiochemotherapy (5-fluorouracil-mitomycin C) has become the standard of care in anal cancer since the '90s. A pooled analysis of individual patient data from 7 major trials was performed quantifying the effect of radiation therapy (RT)-related parameters on the outcome of patients with anal cancer., Materials and Methods: Pooling databases from combined modality trials, the impact of RT parameters (total dose, gap duration, OTT: overall treatment time) on outcome including locoregional failure (LRF), 5-year progression free survival (PFS) and toxicities were investigated. Individual patient data were received for 10/13 identified published studies conducted from 1987 to 2008 (n = 3031). A Cox regression model was used (landmark = 3 months after RT for first follow-up)., Results: After data inspection indicating severe heterogeneity between trials, only 1343 patients from 7/10 studies received were analysed (the most recent ones, since 1994; median follow-up = 4.1 years). A higher overall 5-year LRF rate [22.8% (95% confidence interval [CI] 22.3-27.3%)] significantly correlated with longer OTT (p = 0.03), larger tumour size (p < 0.001) and male gender (p = 0.045). Although significant differences were not observed, subset analyses for LRF (dose range: 50.4-59 Gy) seemed to favour lower doses (p = 0.412), and when comparing a 2-week gap versus 3 (dose: 59.4 Gy), results suggested 3 weeks might be detrimental (p = 0.245). For a 2-week gap versus none (dose range: 55-59.4 Gy), no difference was observed (p = 0.89). Five-year PFS was 65.7% (95% CI: 62.8-68.5%). Higher PFS rates were observed in women (p < 0.001), smaller tumour sizes (p < 0.001) and shorter OTT (p = 0.025). Five-year overall survival [76.7% (95% CI: 73.9%-79.3%)] correlated positively with female gender (p < 0.001), small tumour size (p = 0.027) and short OTT (p = 0.026). Descriptive toxicity data are presented., Conclusion: For patients receiving concurrent external-beam doublet chemoradiation, a longer OTT seems detrimental to outcome. Further trials involving modern techniques may better define optimal OTT and total dose., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Neoadjuvant chemotherapy (CT) followed by radiotherapy (RT) and surgery showed a median survival of 28.7 months in resectable stage IIIB non-small-cell lung cancer (NSCLC) patients (pts). Here, we evaluate the impact of concomitant cetuximab to the same neoadjuvant chemo-radiotherapy (CRT) in selected patients (pts) with NSCLC, stage IIIB., Methods: Resectable stage IIIB NSCLC received three cycles of CT (cisplatin 100 mg/m 2 and docetaxel 85 mg/m 2 d1, q3w) followed by RT (44 Gy in 22 fractions) with concomitant cetuximab (250 mg/m 2 , q1w) and subsequent surgery. The primary endpoint was 1-year progression-free survival (PFS)., Results: Sixty-nine pts were included in the trial. Fifty-seven (83%) pts underwent surgery, with complete resection (R0) in 42 (74%) and postoperative 30 day mortality of 3.5%. Responses were: 57% after CT-cetuximab and 64% after CRT-cetuximab. One-year PFS was 50%. Median PFS was 12.0 months (95% CI: 9.0-15.6), median OS was 21.3 months, with a 2- and 3-yr survival of 41% and 30%, respectively., Conclusions: This is one of the largest prospective phase 2 trial to investigate the role of induction CRT and surgery in resectable stage IIIB disease, and the first adding cetuximab to the neoadjuvant strategy. This trial treatment is feasible with promising response and OS rates, supporting an aggressive approach in selected pts.

Introduction: Long-term data on outcomes of operable stage III NSCLC are scarce., Methods: Individual patient data from 368 patients enrolled in one phase III and two phase II trials were pooled and outcomes after applying the eighth (denoted with an asterisk [*]) versus the sixth TNM staging edition were compared. Patients were treated with either preoperative radiotherapy following 3 cycles of induction chemotherapy (trimodal) or neoadjuvant chemotherapy alone (bimodal)., Results: With the sixth version, the 5- and 10-year survival rates were 38% and 28% for stage IIIA, respectively, and 36% and 24% for stage IIIB, respectively. Factors associated with improved 5-year overall survival were younger age, R0 resection, and pathologic complete remission (pCR) (p = 0.043, p < 0.001 and p = 0.009). With the eighth TNM staging version, 162 patients were moved from stage IIIA to IIIB*. The 5- and 10-year survival rates were 41% and 29% for stage IIIA*, respectively, and 35% and 27% for stage IIIB* patients, respectively. There was no difference in the bi- versus trimodal group with regard to median overall survival (28 months [95% confidence interval (CI): 21-39 months] and 37 months [95% CI: 24-51 months], p = 0.9) and event-free survival (12 months [95% CI: 9-15 months] versus 13 months [95% CI: 10-22 months], p = 0.71)., Conclusions: We showed favorable 10-year survival rates of 29% and 27% in stage IIIA* and IIIB*, respectively. Younger age, R0 resection, and pathologic complete response were associated with improved long-term survival. Outcomes using the sixth versus eighth edition of the TNM classification were similar in operable stage III NSCLC., (Copyright © 2018 International Association for the Study of Lung Cancer. All rights reserved.)

Purpose: To report outcomes of a population of anal cancer patients treated with modern intensity-modulated radiotherapy and daily image-guided radiotherapy techniques., Methods: We analyzed data of 155 patients consecutively treated with intensity-modulated radiotherapy +/- chemotherapy in three radiotherapy departments. One hundred twenty-two patients presented a stage II-IIIA disease. Chemotherapy was administered in 138 patients, mainly using mitomycin C and 5-fluorouracil (n = 81). All patients received 36 Gy (1.8 Gy/fraction) on the pelvic and inguinal nodes, on the rectum, on the mesorectum and on the anal canal, and a sequential boost up to a total dose of 59.4 Gy (1.8 Gy/fraction) on the anal canal and on the nodal gross tumor volumes., Results: Median follow-up was 38 months (interquartile range 12-51). Toxicity data were available for 143 patients: 22% of them presented a G3+ acute toxicity, mainly as moist desquamation (n = 25 patients) or diarrhea (n = 10). Three patients presented a late grade 3 gastrointestinal toxicity (anal incontinence). No grade 4 acute or late toxicity was recorded. Patients treated with fixed-gantry IMRT delivered with a sliding window technique presented a significantly higher risk of acute grade 3 (or more) toxicity compared to those treated with VMAT or helical tomotherapy (38.5 vs 15.3%, p = 0.049). Actuarial 4-year local control rate was 82% (95% CI 76-91%)., Conclusions: Modern intensity-modulated radiotherapy with daily image-guided radiotherapy is effective and safe in treating anal cancer patients and should be considered the standard of care in this clinical setting.

Objectives: To assess the feasibility and efficacy of intensity-modulated radiation implemented with helical tomotherapy image-guided with daily megavoltage computed tomography for head and neck cancer., Methods: Between May 2010 and May 2013, 72 patients were treated with curative intent. The median age was 64 years, with 57% undergoing definitive and 43% postoperative radiotherapy. Primary tumour sites were oral cavity (21%), oropharynx (26%), hypopharynx (20%), larynx (22%), and others (11%). Staging included 4% stage I, 15% II, 26% III, 48% IVa, and 7% IVb. Radiotherapy was combined with chemotherapy in 64%. Primary endpoint was locoregional control, and secondary endpoints survival and toxicity., Results: Median follow-up was 20 months, with 11 locoregional recurrences. Three-year disease-free survival was 58% and overall survival 57%. In the multivariate analysis, age under 64 years, no extracapsular extension, postoperative radiotherapy, induction chemotherapy, and non-oral cavity tumour were significant favourable prognostic factors for disease-free-survival. The overall incidence of acute grade ≥3 toxicities were mucositis 32%, pain 11%, xerostomia 7%, dysphagia 53%, radiodermatitis 44%, and osteonecrosis 1%. Late grade ≥3 toxicities were fibrosis 6%, dysphagia 21%, fistula 1%, and skin necrosis 1%., Conclusions: Intensity-modulated radiation with helical tomotherapy achieved respectable locoregional control and overall survival, with acceptable toxicity, in head and neck cancer patients., (© 2018 S. Karger AG, Basel.)

The synthetic peptide TAT-RasGAP 317-326 has been shown to potentiate the efficacy of anti-cancer drugs. In this study, we explored the action of TAT-RasGAP 317-326 when combined with radiation by investigating its radiosensitizing activity in vitro and in vivo. To investigate the modulation of intrinsic radiosensitivity induced by TAT-RasGAP 317-326 , clonogenic assays were performed using four human cancer cell lines, HCT116 p53 +/+ (ATCC: CCL-247), HCT116 p53 -/- , PANC-1 (ATCC: CRL-1469) and HeLa (ATCC: CCL-2), as well as one nontumor cell line, HaCaT (CLS: 300493). Next, to investigate tumor growth delay after irradiation, HCT116 cell lines were selected and xenografted onto nude mice that were then treated with TAT-RasGAP 317-326 alone or in combination with radiation or cisplatin. Afterwards, cell cycle and death modulation were investigated by quantification of micronuclei and apoptosis-related protein array. TAT-RasGAP 317-326 radiosensitized all four human carcinoma cell lines tested but displayed no effect on normal cells. It also displayed no effect when administered as monotherapy. This radiosensitizing effect was confirmed in vivo in both p53-positive and p53-negative HCT116 xenografts. TAT-RasGAP 317-326 combined with radiation enhanced the number of cells in S phase and subsequently delayed cell death, but had almost no effect on major apoptosis-related proteins. TAT-RasGAP 317-326 is a radiosensitizing agent that acts on carcinoma cells and its radiosensitizing effect might be mediated, at least in part, by the enhancement of mitotic cell death.

Purpose: To provide high-quality and efficient dosimetric planning for various types of stereotactic body radiotherapy (SBRT) for tumor treatment using a multicriteria optimization (MCO) technique fine-tuned with direct machine parameter optimization (DMPO)., Methods and Materials: Eighteen patients with lung (n=11), liver (n=5) or adrenal cell cancer (n=2) were treated using SBRT in our clinic between December 2014 and June 2015. Plans were generated using the RayStation™ Treatment Planning System (TPS) with the VMAT technique. Optimal deliverable SBRT plans were first generated using an MCO algorithm to find a well-balanced tradeoff between tumor control and normal tissue sparing in an efficient treatment planning time. Then, the deliverable plan was post-processed using the MCO solution as the starting point for the DMPO algorithm to improve the dose gradient around the planning target volume (PTV) while maintaining the clinician's priorities. The dosimetric quality of the plans was evaluated using dose-volume histogram (DVH) parameters, which account for target coverage and the sparing of healthy tissue, as well as the CI100 and CI50 conformity indexes., Results: Using a combination of the MCO and DMPO algorithms showed that the treatment plans were clinically optimal and conformed to all organ risk dose volume constraints reported in the literature, with a computation time of approximately one hour. The coverage of the PTV (D99% and D95%) and sparing of organs at risk (OAR) were similar between the MCO and MCO+DMPO plans, with no significant differences (p>0.05) for all the SBRT plans. The average CI100 and CI50 values using MCO+DMPO were significantly better than those with MCO alone (p<0.05)., Conclusions: The MCO technique allows for convergence on an optimal solution for SBRT within an efficient planning time. The combination of the MCO and DMPO techniques yields a better dose gradient, especially for lung tumors., (Copyright © 2016. Published by Elsevier GmbH.)

Multi-criteria optimization provides decision makers with a range of clinical choices through Pareto plans that can be explored during real time navigation and then converted into deliverable plans. Our study shows that dosimetric differences can arise between the two steps, which could compromise the clinical choices made during navigation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and purpose Intensity-modulated radiotherapy (IMRT), also using volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT) techniques, has been only recently introduced for treating anal cancer patients. We report efficacy and safety HT, and daily image-guided RT (IGRT) for anal cancer. Materials and methods We retrospectively analyzed efficacy and toxicity of HT with or without chemotherapy for anal cancer patients. Local control (LC) and grade 3 or more toxicity rate (CTC-AE v.4.0) were the primary endpoints. Overall (OS), disease-free (DFS), and colostomy-free survival (CFS) are also reported. Results Between October 2007 and May 2014, 78 patients were treated. Fifty patients presented a stage II or stage IIIA (UICC 2002), and 33 presented a N1-3 disease. Radiotherapy consisted of 36 Gy (1.8 Gy/fraction) delivered on the pelvis and on the anal canal, with a sequential boost up to 59.4 Gy (1.8 Gy/fraction) delivered to the anal and to nodal gross tumor volumes. Concomitant chemotherapy was delivered in 73 patients, mainly using mitomycin C and 5-fluorouracil (n = 30) or mitomycin C and capecitabine combination (n = 37). After a median follow-up period of 47 months (range 3-75), the five-year LC rate was 83.8% (95% CI 76.2-91.4%). Seven patients underwent a colostomy because of local recurrence (n = 5) or pretreatment dysfunction (n = 2). Overall incidence of grade 3 acute toxicity was 24%, mainly as erythema (n = 15/19) or diarrhea (n = 7/19). Two patients presented a late grade 3 gastrointestinal toxicity (anal incontinence). No grade 4 acute or late toxicity was recorded. Conclusions HT with daily IGRT is efficacious and safe in the treatment of anal canal cancer patients, and is considered in our department standard of care in this clinical setting.

Introduction: External beam radiotherapy (EBRT), with or without androgen deprivation therapy (ADT), is an established treatment option for nonmetastatic prostate cancer. Despite high-level evidence from several randomized trials, risk group stratification and treatment recommendations vary due to contradictory or inconclusive data, particularly with regard to EBRT dose prescription and ADT duration. Our aim was to investigate current patterns of practice in primary EBRT for prostate cancer in Switzerland., Materials and Methods: Treatment recommendations on EBRT and ADT for localized and locally advanced prostate cancer were collected from 23 Swiss radiation oncology centers. Written recommendations were converted into center-specific decision trees, and analyzed for consensus and differences using a dedicated software tool. Additionally, specific radiotherapy planning and delivery techniques from the participating centers were assessed., Results: The most commonly prescribed radiation dose was 78 Gy (range 70-80 Gy) across all risk groups. ADT was recommended for intermediate-risk patients for 6 months in over 80 % of the centers, and for high-risk patients for 2 or 3 years in over 90 % of centers. For recommendations on combined EBRT and ADT treatment, consensus levels did not exceed 39 % in any clinical scenario. Arc-based intensity-modulated radiotherapy (IMRT) is implemented for routine prostate cancer radiotherapy by 96 % of the centers., Conclusion: Among Swiss radiation oncology centers, considerable ranges of radiotherapy dose and ADT duration are routinely offered for localized and locally advanced prostate cancer. In the vast majority of cases, doses and durations are within the range of those described in current evidence-based guidelines.

Background and Purpose: Second mitochondria-derived activator of caspase (SMAC)-mimetics are a new class of targeted drugs that specifically induce apoptotic cancer cell death and block pro-survival signaling by antagonizing selected members of the inhibitor of apoptosis protein (IAP) family., Material and Methods: The present study was designed to investigate the radiosensitizing effect and optimal sequence of administration of the novel SMAC-mimetic Debio 1143 in vitro and in vivo. Apoptosis, alteration of DNA damage repair (DDR), and tumor necrosis factor-alpha (TNF-α) signaling were examined., Results: In vitro, Debio 1143 displayed anti-proliferative activity and enhanced intrinsic radiation sensitivity in 5/6 head and neck squamous cell carcinoma (HNSCC) cell lines in a synergistic manner. In vivo, Debio 1143 dose-dependently radio-sensitized FaDu and SQ20B xenografts, resulting in complete tumor regression in 8/10 FaDu-xenografted mice at the high dose level. At the molecular level, Debio 1143 combined with radiotherapy (RT) induced enhancement of caspase-3 activity, increase in Annexin V-positive cells and karyopyknosis, and increase in TNF-α mRNA levels. Finally, in a neutralization experiment using a TNF-α-blocking antibody and a caspase inhibitor, it was shown that the radiosensitizing effect of Debio 1143 is mediated by caspases and TNF-α., Conclusions: These results demonstrate that the novel SMAC-mimetic Debio 1143 is a radiosensitizing agent that is worthy of further investigation in clinical trials in combination with radiotherapy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The purpose of this work is to evaluate the volumetric-modulated arc therapy (VMAT) multicriteria optimization (MCO) algorithm clinically available in the RayStation treatment planning system (TPS) and its ability to reduce treatment planning time while providing high dosimetric plan quality. Nine patients with localized prostate cancer who were previously treated with 78 Gy in 39 fractions using VMAT plans and rayArc system based on the direct machine parameter optimization (DMPO) algorithm were selected and replanned using the VMAT-MCO system. First, the dosimetric quality of the plans was evaluated using multiple conformity metrics that account for target coverage and sparing of healthy tissue, used in our departmental clinical protocols. The conformity and homogeneity index, number of monitor units, and treatment planning time for both modalities were assessed. Next, the effects of the technical plan parameters, such as constraint leaf motion CLM (cm/°) and maximum arc delivery time T (s), on the accuracy of delivered dose were evaluated using quality assurance passing rates (QAs) measured using the Delta4 phantom from ScandiDos. For the dosimetric plan's quality analysis, the results show that the VMAT-MCO system provides plans comparable to the rayArc system with no statistical difference for V95% (p &lt; 0.01), D1% (p &lt; 0.01), CI (p &lt; 0.01), and HI (p &lt; 0.01) of the PTV, bladder (p &lt; 0.01), and rectum (p &lt; 0.01) constraints, except for the femoral heads and healthy tissues, for which a dose reduction was observed using MCO compared with rayArc (p &lt; 0.01). The technical parameter study showed that a combination of CLM equal to 0.5 cm/degree and a maximum delivery time of 72 s allowed the accurate delivery of the VMAT-MCO plan on the Elekta Versa HD linear accelerator. Planning evaluation and dosimetric measurements showed that VMAT-MCO can be used clinically with the advantage of enhanced planning process efficiency by reducing the treatment planning time without impairing dosimetric quality.

Aims and Background: The standard treatment of anal canal cancer (ACC) is combined chemotherapy and radiation therapy (RT), which is complex because of the shape of the target volumes and the need to minimize the irradiation of normal pelvic structures. In this study we compared the dosimetric results of helical tomotherapy (HT) plans with traditional 3D conformal RT (3DRT) plans for the treatment of ACC., Methods and Study Design: Twelve patients (median age 57 years, range 38-83; F/M 8/4) treated with HT and concurrent chemotherapy for locally advanced ACC were selected. All had histologically confirmed squamous-cell carcinoma. A clinical target volume including the tumor and pelvic and inguinal lymph nodes was treated with HT to a total dose of 36 Gy in 1.8-Gy daily fractions. Then a sequential boost of 23.4 Gy in 1.8-Gy daily fractions (total dose 59.4 Gy) was delivered to the tumor and involved nodes. For all 12 patients, 3DRT plans were generated for comparison. Treatment plans were evaluated by means of standard dose-volume histograms. Dose coverage of the planning target volumes (PTVs), homogeneity index (HI), and mean doses to organs at risk (OARs) were compared., Results: The coverage of PTV was comparable between the two treatment plans. HI was better in the HT vs. 3DRT plans (1.25 and 3.57, respectively; p&lt;0.0001). HT plans resulted in better sparing of OARs (p&lt;0.0001)., Conclusions: HT showed superior target dose conformality and significant sparing of pelvic structures compared with 3DRT. Further investigation should determine if these dosimetric improvements will improve clinical outcomes regarding locoregional control, survival, and treatment-related acute and late morbidity.

The aim of the present study is to assess the disease profile, outcome and prognostic factors in patients treated with surgery combined with radiotherapy (RT), with or without chemotherapy (CXT), for soft-tissue sarcoma (STS) in a multidisciplinary setting. One hundred and sixty-four patients with STS treated between 1980 and 2010 at the Centre Hospitalier Universitaire Vaudois were enrolled in this retrospective study. Seventy-six percent of patients underwent postoperative RT with (24%), or without (52%) CXT, 15% preoperative RT with (5%), or without (10%) CXT, surgery alone (7%), or RT alone (2%) with or without CXT. The median follow-up was 60 months (range 6-292). Local failure was observed in 18%, and distant failure in 21% of the patients. Overall survival (OS), diseasefree survival (DFS), local control (LC) and distant metastases-free survival (DMFS) were 88%, 68%, 83%, and 79% at 5 years, and 80%, 56%, 76%, and 69% at 10 years, respectively. In univariate analyses, favorable prognostic factors for OS, DFS, and DMFS were tumor size 6 cm or less, World Health Organization (WHO)/Zubrod score 0, and stage 2 or less. Age and superficial tumors were favorable only for OS and DMFS respectively. STS involving the extremities had a better outcome regarding DFS and LC. Histological grade 2 or less was favorable for DFS, DMFS, and LC. Radical surgery was associated with better LC and DMFS. RT dose more than 60 Gy was favorable for OS, DFS, and LC. In multivariate analyses, independent factors were age for OS; tumor size for OS, DFS and DMFS; WHO/Zubrod score for OS, DFS and LC; hemoglobin level for DFS; site for DFS and LC; tumor depth for DMFS; histological grade for DFS and LC; surgical procedure for LC and DMFS; and RT dose for OS. This study confirms that in a multidisciplinary setting, STS have a fairly good prognosis. A number of prognostic and predictive factors, including the role of surgery combined with RT, were identified. Regarding RT, a dose of more than 60 Gy was associated with a better outcome, at the price of a higher toxicity. We could not demonstrate a superiority of preoperative RT over postoperative RT.

Background: Sleeve lobectomy is a valid alternative to pneumonectomy for the treatment of centrally located operable non-small cell lung cancer (NSCLC), but concern has been evoked regarding a potentially increased risk of bronchial anastomosis complications after induction therapy. This study examined the impact of induction therapy on airway healing after sleeve lobectomy for NSCLC., Methods: Bronchial anastomosis complications were recorded with respect to the induction regimen applied (neoadjuvant chemotherapy vs chemoradiotherapy) in a consecutive series of patients with sleeve lobectomy for NSCLC., Results: Ninety-nine patients underwent sleeve resection, 28 of them after induction therapy. Twelve patients received chemotherapy alone, and 16 patients had radiochemotherapy. There were no significant differences in postoperative 90-day mortality (3.6% vs 2.8%) and morbidity (54% vs 49%) for patients with and without induction therapy. Bronchial anastomosis complications occurred in 3 patients (10.8%) with neoadjuvant therapy and in 2 (2.8%) without (p = 0.3). In the induction therapy group, two bronchial stenoses occurred after radiochemotherapy and one bronchopleural fistula after chemotherapy alone. In patients without induction therapy, one bronchial stenosis and one bronchopleural fistula were observed. All bronchial stenoses were successfully treated by dilatation, and both bronchopleural fistulas occurring after right lower lobectomy were successfully treated by reoperation and completion sleeve bilobectomy with preservation of the upper lobe., Conclusions: Sleeve lobectomy for NSCLC can be safely performed after induction chemotherapy and radiochemotherapy with mortality and incidence of airway complications similar to that observed in nonpretreated patients. The treatment of airway complications does not differ for patients with and without induction therapy., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The EORTC 22043-30041 trial investigates the role of the addition of androgen suppression to post-operative radiotherapy in patients who have undergone radical prostatectomy. As part of the quality assurance of radiotherapy (QART) a Dummy Run (DR) procedure was performed., Materials and Method: The protocol included detailed and published delineation guidelines. Participating institutions digitally submitted radiotherapy treatment volumes and a treatment plan for a standard clinical case. Submissions were centrally reviewed using the VODCA software platform., Results: Thirty-eight submissions from thirty-one institutions were reviewed. Six were accepted without comments. Twenty-three were accepted with comments on one or more items: target volume delineation (22), OAR delineation (23), planning and dosimetry (3) or treatment verification (1). Nine submissions were rejected requiring resubmission, seven for target volume delineation reasons alone. Intervention to highlight the importance of delineation guidelines was made prior to the entry of the first patient in the trial. After this, a lower percentage of resubmissions was required., Conclusions: The EORTC 22043-30041 Dummy Run highlights the need for timely and effective QART in clinical trials. The variation in target volume and OAR definition demonstrates that clinical guidelines and radiotherapy protocols are not a substitute for QART procedures. Early intervention in response to the Dummy Run improved protocol understanding., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: To make a comprehensive evaluation of organ-specific out-of-field doses using Monte Carlo (MC) simulations for different breast cancer irradiation techniques and to compare results with a commercial treatment planning system (TPS)., Materials and Methods: Three breast radiotherapy techniques using 6MV tangential photon beams were compared: (a) 2DRT (open rectangular fields), (b) 3DCRT (conformal wedged fields), and (c) hybrid IMRT (open conformal+modulated fields). Over 35 organs were contoured in a whole-body CT scan and organ-specific dose distributions were determined with MC and the TPS., Results: Large differences in out-of-field doses were observed between MC and TPS calculations, even for organs close to the target volume such as the heart, the lungs and the contralateral breast (up to 70% difference). MC simulations showed that a large fraction of the out-of-field dose comes from the out-of-field head scatter fluence (>40%) which is not adequately modeled by the TPS. Based on MC simulations, the 3DCRT technique using external wedges yielded significantly higher doses (up to a factor 4-5 in the pelvis) than the 2DRT and the hybrid IMRT techniques which yielded similar out-of-field doses., Conclusions: In sharp contrast to popular belief, the IMRT technique investigated here does not increase the out-of-field dose compared to conventional techniques and may offer the most optimal plan. The 3DCRT technique with external wedges yields the largest out-of-field doses. For accurate out-of-field dose assessment, a commercial TPS should not be used, even for organs near the target volume (contralateral breast, lungs, heart)., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Induction radiochemotherapy, followed by resection, for T4 non-small cell lung cancer, has shown promising long-term survival but may be associated with increased postoperative morbidity and death, depending on patient selection. Here, we determined the effect of induction radiochemotherapy on pulmonary function and whether postinduction pulmonary function changes predict hospital morbidity and death and long-term survival., Methods: A consecutive prospective cohort of 72 patients with T4 N0-2 M0 non-small cell lung cancer managed by radiochemotherapy, followed by resection, is reported. All patients underwent thoracoabdominal computed tomography or fusion positron emission tomography-computed tomography, brain imaging, mediastinoscopy, echocardiography, ventilation-perfusion scintigraphy, and pulmonary function testing before and after induction therapy. Resection was performed if the postoperative forced expiratory volume in 1 second and diffusion capacity of the lung for carbon monoxide exceeded 30% predicted and if the postoperative maximum oxygen consumption exceeded 10 mL/kg/min., Results: The postoperative 90-day mortality rate was 8% (lobectomy, 2%; pneumonectomy, 21%; p=0.01). All deaths after pneumonectomy occurred after right-sided procedures. The 3-year and 5-year survival was 50% (95% confidence interval, 36% to 62%) and 45% (95% confidence interval, 31% to 57%) and was significantly associated with completeness of resection (p=0.004) and resection type (pneumonectomy vs lobectomy, p=0.01). There was no correlation between postinduction pulmonary function changes and postoperative morbidity or death or long-term survival in patients managed by lobectomy or pneumonectomy., Conclusions: In properly selected patients with T4 N0-2 M0 non-small cell lung cancer, resection after induction radiochemotherapy can be performed with a reasonable postoperative mortality rate and long-term survival, provided the resection is complete and a right-sided pneumonectomy is avoided. Postinduction pulmonary function changes did not correlate with postoperative morbidity or death or with long-term outcome., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Quality assurance (QA) in clinical trials is essential to ensure treatment is safely and effectively delivered. As QA requirements have increased in complexity in parallel with evolution of radiation therapy (RT) delivery, a need to facilitate digital data exchange emerged. Our objective is to present the platform developed for the integration and standardization of QART activities across all EORTC trials involving RT., Methods: The following essential requirements were identified: secure and easy access without on-site software installation; integration within the existing EORTC clinical remote data capture system; and the ability to both customize the platform to specific studies and adapt to future needs. After retrospective testing within several clinical trials, the platform was introduced in phases to participating sites and QART study reviewers., Results: The resulting QA platform, integrating RT analysis software installed at EORTC Headquarters, permits timely, secure, and fully digital central DICOM-RT based data review. Participating sites submit data through a standard secure upload webpage. Supplemental information is submitted in parallel through web-based forms. An internal quality check by the QART office verifies data consistency, formatting, and anonymization. QART reviewers have remote access through a terminal server. Reviewers evaluate submissions for protocol compliance through an online evaluation matrix. Comments are collected by the coordinating centre and institutions are informed of the results., Conclusions: This web-based central review platform facilitates rapid, extensive, and prospective QART review. This reduces the risk that trial outcomes are compromised through inadequate radiotherapy and facilitates correlation of results with clinical outcomes., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The implementation of new techniques of imaging in the daily practice of the radiation oncologist is a major advance in these last 10 years. This allows optimizing the therapeutic intervals and locoregional control of the disease while limiting side effects. Among them, positron emission tomography (PET) offers an opportunity to the clinician to obtain data relative to the tumoral biological mechanisms, while benefiting from the morphological images of the computed tomography (CT) scan. Recently hybrid PET/CT has been developed and numerous studies aimed at optimizing its use in the planning, the evaluation of the treatment response and the prognostic value. The choice of the radiotracer (according to the type of cancer and to the studied biological mechanism) and the various methods of tumoral delineation, require a regular update to optimize the practices. We propose throughout this article, an exhaustive review of the published researches (and in process of publication) until December 2011, as user guide of PET/CT in all the aspects of the modern radiotherapy (from the diagnosis to the follow-up): biopsy guiding, optimization of treatment planning and dosimetry, evaluation of tumor response and prognostic value, follow-up and early detection of recurrence versus tumoral necrosis. In a didactic purpose, each of these aspects is approached by primary tumoral location, and illustrated with representative iconographic examples. The current contribution of PET/CT and its perspectives of development are described to offer to the radiation oncologist a clear and up to date reading in this expanding domain., (Copyright © 2012. Published by Elsevier SAS.)

We report 4 patients with stage IVA thymic tumors who underwent extrapleural pneumonectomy and thymectomy with venous confluence resection using a temporary percutaneous venous jugular-femoral bypass technique. The superior vena cava was replaced in 2 patients, and the innominate vein was resected in 2 patients. Complete tumor resection was obtained in all patients. There was no 90-day postoperative mortality. One patient died at 6 months postoperatively of an unrelated cause, without recurrent disease, and 3 are alive and disease-free with a follow-up ranging from 19 to 80 months. Extrapleural pneumonectomy can be combined with thymectomy and venous confluence resection for stage IVA thymic tumors., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the outcome in patients with olfactory neuroblastoma (ONB)., Methods and Materials: Seventy-seven patients treated for nonmetastatic ONB between 1971 and 2004 were included. According to Kadish classification, there were 11 patients with Stage A, 29 with Stage B, and 37 with Stage C. T-classification included 9 patients with T1, 26 with T2, 16 with T3, 15 with T4a, and 11 with T4b tumors. Sixty-eight patients presented with N0 (88%) disease., Results: Most of the patients (n = 56, 73%) benefited from surgery (S), and total excision was possible in 44 patients (R0 in 32, R1 in 13, R2 in 11). All but five patients benefited from RT, and chemotherapy was given in 21 (27%). Median follow-up period was 72 months (range, 6-315). The 5-year overall survival (OS), disease-free survival (DFS), locoregional control, and local control were 64%, 57%, 62%, and 70%, respectively. In univariate analyses, favorable factors were Kadish A or B disease, T1-T3 tumors, no nodal involvement, curative surgery, R0/R1 resection, and RT-dose 54 Gy or higher. Multivariate analysis revealed that the best independent factors predicting the outcome were T1-T3, N0, R0/R1 resection, and total RT dose (54 Gy or higher)., Conclusion: In this multicenter retrospective study, patients with ONB treated with R0 or R1 surgical resection followed by at least 54-Gy postoperative RT had the best outcome. Novel strategies including concomitant chemotherapy and/or higher dose RT should be prospectively investigated in this rare disease for which local failure remains a problem., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Head and neck squamous cell carcinomas are frequently diagnosed at an advanced stage. Their treatment remains controversial, and has to be multidisciplinary. External beam radiotherapy is a recognized treatment option after radical curative surgery in order to improve local control. Different adjuvant treatment options have been studied in order to improve the outcome of these patients. We review in this paper the different prognostic factors indicating an adjuvant treatment and the interest of treatment intensification in bad prognostic patients., (2010 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Introduction: The EORTC 22922/10925 trial investigated the potential survival benefit and toxicity of elective irradiation of the internal mammary and medial supraclavicular (IM-MS) nodes Accrual completed in January 2004 and first results are expected in 2012. We present the toxicity reported until year 3 after treatment., Patients and Methods: At each visit, toxicity was reported but severity was not graded routinely. Toxicity rates and performance status (PS) changes at three years were compared by chi(2) tests and logistic regression models in all the 3,866 of 4,004 patients eligible to the trial who received the allocated treatment., Results: Only lung (fibrosis; dyspnoea; pneumonitis; any lung toxicities) (4.3% vs. 1.3%; p < 0.0001) but not cardiac toxicity (0.3% vs. 0.4%; p = 0.55) significantly increased with IM-MS treatment. No significant worsening of the PS was observed (p = 0.79), suggesting that treatment-related toxicity does not impair patient's daily activities., Conclusions: IM-MS irradiation seems well tolerated and does not significantly impair WHO PS at three years. A follow-up period of at least 10 years is needed to determine whether cardiac toxicity is increased after radiotherapy.

Purpose: The Gastro-Intestinal Working Party of the EORTC Radiation Oncology Group (GIWP-ROG) developed guidelines for target volume definition in neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction (GEJ) and the stomach., Methods and Materials: Guidelines about the definition of the clinical target volume (CTV) are based on a systematic literature review of the location and frequency of local recurrences and lymph node involvement in adenocarcinomas of the GEJ and the stomach. Therefore, MEDLINE was searched up to August 2008. Guidelines concerning prescription, planning and treatment delivery are based on a consensus between the members of the GIWP-ROG., Results: In order to support a curative resection of GEJ and gastric cancer, an individualized preoperative treatment volume based on tumour location has to include the primary tumour and the draining regional lymph nodes area. Therefore we recommend to use the 2nd English Edition of the Japanese Classification of Gastric Carcinoma of the Japanese Gastric Cancer Association which developed the concept of assigning tumours of the GEJ and the stomach to anatomically defined sub-sites corresponding respectively to a distinct lymphatic spread pattern., Conclusion: The GIWP-ROG defined guidelines for preoperative irradiation of adenocarcinomas of the GEJ and the stomach to reduce variability in the framework of future clinical trials.

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

Introduction: To report acute and late toxicities in patients with intermediate- and high-risk prostate cancer treated with combined high-dose-rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT)., Materials and Methods: From March 2003 to September 2005, 64 men were treated with a single implant HDR-B with 21 Gy given in three fractions, followed by 50 Gy IMRT along with organ tracking. Median age was 66.1 years, and risk of recurrence was intermediate in 47% of the patients or high in 53% of the patients. Androgen deprivation therapy was received by 69% of the patients. Toxicity was scored according to the CTCAE version 3.0. Median follow-up was 3.1 years., Results: Acute grade 3 genitourinary (GU) toxicity was observed in 7.8% of the patients, and late grades 3 and 4 GU toxicity was observed in 10.9% and 1.6% of the patients. Acute grade 3 gastrointestinal (GI) toxicity was experienced by 1.6% of the patients, and late grade 3 GI toxicity was absent. The urethral V(120) (urethral volume receiving > or =120% of the prescribed HDR-B dose) was associated with acute (P=.047) and late > or = grade 2 GU toxicities (P=.049)., Conclusions: Late grades 3 and 4GU toxicity occurred in 10.9% and 1.6% of the patients after HDR-B followed by IMRT in association with the irradiated urethral volume. The impact of V(120) on GU toxicity should be validated in further studies.

Aim: To assess the influence of hemoglobin (Hb) levels in locally advanced head and neck cancer (LAHNC) patients treated with surgery and postoperative radiotherapy (PORT)., Material and Methods: Pre- and postoperative Hb levels were collected in 79 patients treated with surgery followed by accelerated PORT for LAHNC. Median follow-up was 52 months (range 12-95 months)., Results and Discussion: Four-year overall survival (OS) rate was 51%. Neither pre- nor postoperative Hb level (<120 or 130 g/l in women or men, respectively) influenced the outcome. However, when Hb decrease between pre- and postoperative Hb values was taken into account, 4-year OS was significantly higher in patients with Hb difference less than 38 g/l (quartile value) compared with those with Hb decrease 38 g/l or more (61% versus 16%, P = 0.008)., Conclusion: Decrease in Hb level by more than 38 g/l after surgery secondary to blood loss influences the outcome when postoperative RT is indicated.

Introduction: EORTC trial 22991 was designed to evaluate the addition of concomitant and adjuvant short-term hormonal treatments to curative radiotherapy in terms of disease-free survival for patients with intermediate risk localized prostate cancer. In order to assess the compliance to the 3D conformal radiotherapy protocol guidelines, all participating centres were requested to participate in a dummy run procedure. An individual case review was performed for the largest recruiting centres as well., Materials and Methods: CT-data of an eligible prostate cancer patient were sent to 30 centres including a description of the clinical case. The investigator was requested to delineate the volumes of interest and to perform treatment planning according to the protocol. Thereafter, the investigators of the 12 most actively recruiting centres were requested to provide data on five randomly selected patients for an individual case review., Results: Volume delineation varied significantly between investigators. Dose constraints for organs at risk (rectum, bladder, hips) were difficult to meet. In the individual case review, no major protocol deviations were observed, but a number of dose reporting problems were documented for centres using IMRT., Conclusions: Overall, results of this quality assurance program were satisfactory. The efficacy of the combination of a dummy run procedure with an individual case review is confirmed in this study, as none of the evaluated patient files harboured a major protocol deviation. Quality assurance remains a very important tool in radiotherapy to increase the reliability of the trial results. Special attention should be given when designing quality assurance programs for more complex irradiation techniques.

Squamous-cell carcinoma of the head and neck are neoplasic diseases for which locoregional control remains very important, given its particular pattern of failure. Treatment of early stage disease involves surgery or radiation therapy. Locally advanced disease is treated either with concurrent chemoradiotherapy or surgery followed by radio-chemotherapy, according to each center's expertise. Recent research has demonstrated that the overexpression of epidermal growth factor receptor (EGFR) is associated with tumor progression. Based on this research, a new type of anticancer therapy, so-called "targeted therapies" represent important additions to the current therapeutic arsenal in the management of head and neck cancers, based on results of a phase III trial combining radiotherapy and immunotherapy with cetuximab.