High-dose radiotherapy and risk-adapted androgen deprivation in localised prostate cancer (DART 01/05): 10-year results of a phase 3 randomised, controlled trial.

BACKGROUND: The optimal duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains controversial. The DART 01/05 trial was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. The 5-year results showed that 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy significantly improved biochemical control, metastasis, and overall survival, especially in patients with high-risk disease. In this report, we present the 10-year final results of the trial. METHODS: This open-label, phase 3, randomised, controlled trial was done in ten hospitals in Spain. The eligibility criteria included patients aged 18 years or older with histologically confirmed T1c to T3, N0, and M0 adenocarcinoma of the prostate, according to the 2002 classification of the American Joint Committee on Cancer, with intermediate-risk and high-risk factors, prostate-specific antigen (PSA) less than 100 ng/mL, and a Karnofsky performance score of at least 70%. Patients were randomly assigned (1:1) to receive 4 months of neoadjuvant and concomitant short-term androgen deprivation (STAD) plus high-dose radiotherapy (minimum dose 76 Gy; median dose 78 Gy) or to receive the same treatment followed by 24 months of adjuvant long-term androgen deprivation (LTAD), via a randomisation scheduled generated by Statistical Analysis Software programme (version 9.1) and an interactive web response system. Patients assigned to the STAD group received 4 months of neoadjuvant and concomitant androgen deprivation (oral flutamide 750 mg per day or oral bicalutamide 50 mg per day) with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy was added during the first 2 months of treatment. Patients assigned to LTAD continued with goserelin every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival at 5 years. For this 10-year study we analysed overall survival, metastasis-free survival, biochemical disease-free survival, and cause-specific survival. Analysis was by intention to treat. This trial is closed and is registered at ClinicalTrials.gov (NCT02175212) and in the EU Clinical Trials Register (EudraCT 2005-000417-36). FINDINGS: Between Nov 7, 2005, and Dec 20, 2010, 355 patients were enrolled. One patient in the STAD group withdrew from the trial, hence 354 participants were randomly assigned to STAD (n=177) or LTAD (n=177). The median follow-up was 119·4 months (IQR 100·6-124·3). The 10-year biochemical disease-free survival for LTAD was 70·2% (95% CI 63·1-77·3) and for STAD was 62·3% (54·9-69·7; hazard ratio [HR] 0·84; 95% CI 0·50-1·43; p=0·52). At 10 years, overall survival was 78·4% (72·1-84·8) for LTAD and 73·3% (66·6-80·0) for STAD (HR 0·84; 95% CI 0·55-1·27; p=0·40), and metastasis-free survival was 76·0% (69·4-82·7) for LTAD and 70·9% (64·0-77·8) for STAD (HR 0·90; 95% CI, 0·37-2·19; p=0·81). For the subgroup of high-risk patients, the 10-year biochemical disease-free survival was 67·2% (57·2-77·2) for LTAD and 53·7% (43·3-64·1) for STAD (HR 0·90; 95% CI 0·49-1·64; p=0·73), the 10-year overall survival was 78·5% (69·6-87·3) for LTAD and 67·0% (57·3-76·7) for STAD (HR 0·58; 95% CI 0·33-1·01; p=0·054), and the 10-year metastasis-free survival was 76·6% (95% CI 67·6-85·6) for LTAD and 65·0% (55·1-74·8) for STAD (HR 0·89; 95% CI 0·33-2·43; p=0·82). Only 11 (3%) of 354 patients died from prostate cancer, all of them in the high-risk subgroup (five in the LTAD group and six in the STAD group). 76 (21%) patients died from other causes (mainly second malignancies in 31 [9%] and cardiovascular disease in 21 [6%]). No treatment-related deaths were observed. INTERPRETATION: After an extended 10-year follow-up, we were unable to support the significant benefit of LTAD reported at 5 years. However, the magnitude of the benefit was clinically relevant in high-risk patients. Intermediate-risk patients treated with high-dose radiotherapy do not benefit from LTAD. A biological characterisation with the inclusion of genomic testing is needed in the decision-making process. FUNDING: Grupo de Investigación en Oncología Radioterápica and Sociedad Española de Oncología Radioterápica, the National Health Investigation Fund, and AstraZeneca.

Adjuvant chemoradiation in pancreatic cancer: impact of radiotherapy dose on survival.

BACKGROUND: To evaluate the impact of radiation dose on overall survival (OS) in patients treated with adjuvant chemoradiation (CRT) for pancreatic ductal adenocarcinoma (PDAC). METHODS: A multicenter retrospective analysis on 514 patients with PDAC (T1-4; N0-1; M0) treated with surgical resection with macroscopically negative margins (R0-1) followed by adjuvant CRT was performed. Patients were stratified into 4 groups based on radiotherapy doses (group 1: < 45 Gy, group 2: ≥ 45 and < 50 Gy, group 3: ≥ 50 and < 55 Gy, group 4: ≥ 55 Gy). Adjuvant chemotherapy was prescribed to 141 patients. Survival functions were plotted using the Kaplan-Meier method and compared through the log-rank test. RESULTS: Median follow-up was 35 months (range: 3-120 months). At univariate analysis, a worse OS was recorded in patients with higher preoperative Ca 19.9 levels (≥ 90 U/ml; p < 0.001), higher tumor grade (G3-4, p = 0.004), R1 resection (p = 0.004), higher pT stage (pT3-4, p = 0.002) and positive nodes (p < 0.001). Furthermore, patients receiving increasing doses of CRT showed a significantly improved OS. In groups 1, 2, 3, and 4, median OS was 13.0 months, 21.0 months, 22.0 months, and 28.0 months, respectively (p = 0.004). The significant impact of higher dose was confirmed by multivariate analysis. CONCLUSIONS: Increasing doses of CRT seems to favorably impact on OS in adjuvant setting. The conflicting results of randomized trials on adjuvant CRT in PDAC could be due to < 45 Gy dose generally used.

Intraoperative Electron Radiation Therapy Combined with External Beam Radiation Therapy after Gross Total Resection in Extremity Soft Tissue Sarcoma: A European Pooled Analysis.

INTRODUCTION: We report a pooled analysis evaluating the combination of gross complete limb-sparing surgery, intraoperative electron radiation therapy (IOERT), and external beam radiation therapy (EBRT) in patients with extremity soft tissue sarcoma (STS). METHODS: Individual data of 259 patients (median follow-up 63 months) with extremity STS from three European expert centers were pooled. Median age was 55 years and median tumor size was 8 cm. Eighty percent of patients presented with primary disease, mainly located in the lower limb (81%). Union for International Cancer Control 7th edition stage at presentation was as follows: stage I: 9%; stage II: 47%; stage III: 39%; stage IV: 5%. Most patients showed high-grade lesions (91%), predominantly liposarcoma (31%). Median IOERT dose was 12 Gy, preceeded (17%) or followed (83%) by EBRT, with a median dose of 45 Gy. RESULTS: Surgery resulted in R0 resections in 71% of patients and R1 resections in 29% of patients. The 5-year local control (LC) rate was 86%, and significant factors in univariate analysis were disease status and resection margin. Only margin remained significant in multivariate analysis. The 5-year distant control rate was 69%, and significant factors in univariate analysis were histology, grading, resection margin, and metastases prior to/at IOERT. Only grading and metastases remained significant in multivariate analysis. Actuarial 5-year rates of freedom from treatment failure and OS were 61% and 78%, respectively. Significant factors for OS were grading and metastases prior to/at IOERT (univariate, multivariate). Limb preservation and good functional outcome were achieved in 95% and 81% of patients. CONCLUSIONS: Our pooled analysis confirmed prior reports of encouraging LC and survival, with excellent rates of preserved limb function with this treatment approach. Resection margin remained the most important factor for LC, while grading and metastases prior to/at IOERT mainly predicted survival.

Metabolic and molecular relative percentage coreduction in patients with locally advanced rectal cancer treated with neoadjuvant therapy.

PURPOSE: Vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor-1 (EGFR) and cyclooxygenase-2 (COX-2) stimulate key processes involved in tumour progression and are important targets for cancer therapeutics. (18)F-FDG maximum standardized uptake value (SUVmax) on PET/CT is a marker of tumour metabolic activity. The purpose of this study was to measure percentage reductions in SUVmax (∆SUVmax%), VEGFR-2 (∆VEGFR-2%), EGFR (∆EGFR%) and COX-2 (∆COX-2%) in patients with locally advanced rectal cancer (LARC) after preoperative treatment, and to correlate the changes in these markers of response with pathological response in terms of tumour regression grade (TRG) using Rödel's scale and long-term clinical outcome. METHODS: VEGFR-2, EGFR and COX-2 were measured using a quantitative and qualitative compound immunohistochemistry analysis (immunoreactive score) of the pretreatment endoscopic biopsy and definitive surgical specimens. Composite indexes using ∆SUVmax% and the three molecules were developed to differentiate patients with metabolic and molecular responses from nonresponders. Cox proportional hazards model was used to explore associations between the tumour markers, disease-free survival (DFS) and overall survival (OS). RESULTS: The analysis included 38 patients with a median follow-up of 86 months (range 5 - 113 months). The ∆VEGFR-2%/∆SUVmax% index correctly identified 13 of 19 pathological responders (TRG 3 and 4) and 17 of 19 nonresponders (TRG 0 - 2) (sensitivity 68 %, specificity 89 %, accuracy 79 %, positive predictive value 87 %, negative predictive value 74 %). In multivariate analysis, only the ∆VEGFR-2%/∆SUVmax% index was associated with DFS (HR 0.11, p = 0.001) and OS (HR 0.15, p = 0.02). CONCLUSION: In patients with LARC the ∆VEGFR-2%/∆SUVmax% response index is associated with outcome. Determination of the optimal diagnostic cut-off level for this novel biomarker association should be explored. Evaluation in a clinical trial is required to determine whether selected patients could benefit from treatment with a VEGFR-targeted therapeutic agent.

High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial.

BACKGROUND: The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation was superior to short-term androgen deprivation when combined with high-dose radiotherapy. METHODS: In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c-T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175212. FINDINGS: Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short-term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% [95% CI 87-92] vs 81% [78-85]; hazard ratio [HR] 1·88 [95% CI 1·12-3·15]; p=0·01). 5-year overall survival (95% [95% CI 93-97] vs 86% [83-89]; HR 2·48 [95% CI 1·31-4·68]; p=0·009) and 5-year metastasis-free survival (94% [95% CI 92-96] vs 83% [80-86]; HR 2·31 [95% CI 1·23-3·85]; p=0·01) were also significantly better in the long-term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3-4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported. INTERPRETATION: Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation. FUNDING: Spanish National Health Investigation Fund, AstraZeneca.

Adjuvant chemotherapy in rectal cancer: defining subgroups who may benefit after neoadjuvant chemoradiation and resection: a pooled analysis of 3,313 patients.

Recent literature suggests that the benefit of adjuvant chemotherapy (aCT) for rectal cancer patients might depend on the response to neoadjuvant chemoradiation (CRT). Aim was to evaluate whether the effect of aCT in rectal cancer is modified by response to CRT and to identify which patients benefit from aCT after CRT, by means of a pooled analysis of individual patient data from 13 datasets. Patients were categorized into three groups: pCR (ypT0N0), ypT1-2 tumour and ypT3-4 tumour. Hazard ratios (HR) for the effect of aCT were derived from multivariable Cox regression analyses. Primary outcome measure was recurrence-free survival (RFS). One thousand seven hundred and twenty three (1723) (52%) of 3,313 included patients received aCT. Eight hundred and ninety eight (898) patients had a pCR, 966 had a ypT1-2 tumour and 1,302 had a ypT3-4 tumour. For 122 patients response, category was missing and 25 patients had ypT0N+. Median follow-up for all patients was 51 (0-219) months. HR for RFS with 95% CI for patients treated with aCT were 1.25(0.68-2.29), 0.58(0.37-0.89) and 0.83(0.66-1.10) for patients with pCR, ypT1-2 and ypT3-4 tumours, respectively. The effect of aCT in rectal cancer patients treated with CRT differs between subgroups. Patients with a pCR after CRT may not benefit from aCT, whereas patients with residual tumour had superior outcomes when aCT was administered. The test for interaction did not reach statistical significance, but the results support further investigation of a more individualized approach to administer aCT after CRT and surgery based on pathologic staging.

Single-Institution Multidisciplinary Management of Locoregional Oligo-Recurrent Pelvic Malignancies: Long-Term Outcome Analysis.

PURPOSE: The aim of this study was to analyze long-term outcomes and prognostic factors associated with survival in patients with locoregional oligo-recurrent (LROR) pelvic malignancies treated in a multimodal protocol. METHODS: Patients with an histologic diagnosis of LROR pelvic cancer (rectal 50 %, gynecological 50 %) with absence of distant metastases, undergoing surgery with radical intent and intraoperative radiotherapy (median dose 12.5 Gy) were considered eligible for participation in this study. Additionally, 48 % received external beam radiotherapy (EBRT) (median dose 50 Gy). RESULTS: From 1995 to 2012, a total of 143 patients from a single institution were analyzed. With a median follow-up time of 48 months (range 2-189), 5-year locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) were 53, 44, and 46 %, respectively. On multivariate analysis, no EBRT treatment to the locoregional (p ≤ 0.001), R1 margin status (p = 0.03), time interval from primary tumor diagnosis to LROR <24 months (p = 0.05), and fragmentation in the resected specimen (p = 0.004) retained significance in relation to LRC. On multivariate analysis we found that only R1 margin status (p = 0.003), primary tumor diagnosis to LROR <24 months (p = 0.02), and high histological grade (p = 0.02) were significantly associated with OS. CONCLUSIONS: From this analysis emerges the fact that EBRT influences local control but, given the high risk of distant metastases, DFS remains modest. Margin status, tumor fragmentation, no EBRT to the LR, and time interval from primary tumor diagnosis to LROR are the dominant factors for subsequent locoregional recurrence (LRR). Accordingly, future prospective studies might be designed which adapt treatment according to the predicted risk of subsequent LRR.

Role of radiotherapy in the chemotherapy-containing multidisciplinary management of patients with resected pancreatic adenocarcinoma.

BACKGROUND: To analyze prognostic factors associated with long-term outcomes in patients with resected pancreatic cancer treated with chemotherapy (CT) and surgery with or without external beam radiotherapy (EBRT). PATIENTS AND METHODS: From January 1995 to December 2012, 95 patients with adenocarcinoma of the pancreas and locoregional disease [clinical stage IB-IIA (n = 45; 47%), IIB-IIIC (n = 50; 53%)] were treated with curative resection [R0 (n = 52; 55%), R1 (n = 43, 45%)] and CT with (n = 60; 63%) or without (n = 35; 37%) EBRT (45-50.4 Gy). Additionally, 29 patients (48%) also received a pre-anastomosis IOERT boost (applicator diameter size, 7-10 cm; dose, 10-15 Gy; beam energy, 9-18 MeV). RESULTS: With a median follow-up of 17.2 months (range, 1-182), 2-year overall survival (OS), disease-free survival (DFS), and locoregional control were 28, 20, and 53%, respectively. Univariate analyses showed that IIB-IIIC stage (HR, 2.23; p = 0.04), R1 margin resection status (HR, 2.09; p = 0.04), no vascular resection (HR, 0.42; p = 0.02), and not receiving external beam radiotherapy (HR, 2.70; p = 0.004) were associated with locoregional recurrence. In the multivariate analysis, only R1 margin resection status (HR, 2.63; p = 0.009) and not receiving EBRT (HR, 2.91; p = 0.002) retained significance with regard to locoregional recurrence. We observed no difference in toxicity between patients treated with or without EBRT (p = 0.44). Overall treatment mortality was 3%. No long-term treatment-related death occurred. CONCLUSIONS: Although adjuvant CT is still the standard of care for resected pancreatic tumors, OS remains modest owing to the high risk of distant metastases. Locoregional treatment needs to be tested in the context of more efficient systemic therapy.

Human cytomegalovirus and Epstein-Barr virus infection impact on (18)F-FDG PET/CT SUVmax, CT volumetric and KRAS-based parameters of patients with locally advanced rectal cancer treated with neoadjuvant therapy.

PURPOSE: It has long been debated whether human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) are associated with rectal cancer. The gene products of HCMV and EBV contribute to cell-cycle progression, mutagenesis, angiogenesis and immune evasion. The aim of this prospective study was to analyse the association between infection of a tumour by HCMV and EBV and clinical, histological, metabolic ((18)F-FDG uptake), volumetric (from CT) and molecular (KRAS status) features and long-term outcomes in a homogeneously treated group of patients with locally advanced rectal cancer. METHODS: HCMV and EBV were detected in pretreatment biopsies using polymerase chain reaction (PCR). The Cox proportional hazards regression model was used to explore associations between viral infection and disease-free survival (DFS) and overall survival (OS). RESULTS: We analysed 37 patients with a median follow-up of 74 months (range 5-173 months). Locoregional control, OS and DFS at 5 years were 93%, 74% and 71%, respectively. Patients with HCMV/EBV coinfection had a significantly higher maximum standardized uptake value than patients without viral coinfection (p = 0.02). Significant differences were also observed in staging and percentage relative reduction in tumour volume between patients with and without HCMV infection (p < 0.01) and EBV infection (p < 0.01). KRAS wildtype status was significantly more frequently observed in patients with EBV infection (p <0.01) and HCMV/EBV co-infection (p = 0.04). No significant differences were observed in OS or DFS between patients with and without EBV infection (p = 0.88 and 0.73), HCMV infection (p = 0.84 and 0.79), and EBV/CMV coinfection (p = 0.24 and 0.39). CONCLUSION: This pilot study showed that viral infections were associated with metabolic staging differences, and differences in the evolution of metabolic and volumetric parameters and KRAS mutations. Further findings of specific features will help determine the best candidates for metabolic and volumetric staging and restaging. Further toxicity profile findings will help to determine the best candidates for specific supportive treatment during pelvic chemoradiotherapy in patients with locally advanced rectal cancer.

Intraoperative radiotherapy for gastrointestinal malignancies: contemporary outcomes with multimodality therapy.

The integration of intraoperative radiotherapy (IORT) into the multimodal treatment of gastrointestinal cancer is feasible and leads to high rates of local control. In-field tumoral control using IORT-containing strategies can be achieved in over 90 % of most cases, regardless of the site or status of the tumor (primary or recurrent). Electron beam IORT, or intraoperative electron radiation therapy, is the dominant technology used in institutions reporting data in publications the 21st century. Neither surgery nor systemic therapy is compromised by the integration of IORT-containing radiotherapy.

Bibliometrics of intraoperative radiotherapy: analysis of technology, practice and publication tendencies.

PURPOSE: To analyze the performance and quality of intraoperative radiation therapy (IORT) publications identified in medical databases during a recent period in terms of bibliographic metrics. MATERIALS AND METHODS: A bibliometric search was conducted for IORT papers published in the PubMed database between 1997 and 2013. Publication rate was used as a quantity indicator; the 2012 Science Citation Index Impact Factor as a quality indicator. Furthermore, the publications were stratified in terms of study type, scientific topic reported, year of publication, tumor type and journal specialty. We performed a one-way analysis of variance (ANOVA) to determine differences between the means of the analyzed groups. RESULTS: Among the total of 207 journals, articles were reported significantly more frequently in surgery (n = 399, 41 %) and radiotherapy journals (n = 273, 28 %; p < 0.01). The highest impact factor was achieved by clinical oncology journals (p < 0.01). The majority of identified articles were retrospective cohort reports (n = 622, 64 %), followed by review articles (n = 204, 21 %; p < 0.001). Regarding primary topic, reports on cancer outcome following specific tumor therapy were most frequently published (n = 661, 68 %; p < 0.001) and gained the highest mean impact factor (p < 0.01). Gastrointestinal tumor reports were represented most frequently (n = 456, 47 %; p < 0.001) and the mean superior impact factor was earned by breast and gynecologic publications (p < 0.01). CONCLUSION: We identified a consistent and sustained scientific productivity of international IORT expert groups. Most publications appeared in journals with surgical and radiooncological content. The highest impact factor was achieved by medical oncology journals.

Limb-sparing management with surgical resection, external-beam and intraoperative electron-beam radiation therapy boost for patients with primary soft tissue sarcoma of the extremity: a multicentric pooled analysis of long-term outcomes.

BACKGROUND OR PURPOSE: A joint analysis of data from three contributing centres within the intraoperative electron-beam radiation therapy (IOERT) Spanish program was performed to investigate the main contributions of IORT to the multidisciplinary treatment of high-risk extremity soft tissue sarcoma (STS). METHODS AND MATERIALS: Patients with an histologic diagnosis of primary extremity STS, with absence of distant metastases, undergoing limb-sparing surgery with radical intent, external beam radiotherapy (median dose 45 Gy) and IOERT (median dose 12.5 Gy) were considered eligible for participation in this study. RESULTS: From 1986-2012, a total of 159 patients were analysed in the study from three Spanish institutions. With a median follow-up time of 53 months (range 4-316 years), 5-year local control (LC) was 82 %. The 5-year IOERT in-field control, disease-free survival (DFS) and overall survival (OS) were 86, 62 and 72 %, respectively. On multivariate analysis, only microscopically involved margin (R1) resection status retained significance in relation to LC (HR 5.20, p < 0.001). With regard to IOERT in-field control, incomplete resection (HR 4.88, p = 0.001) and higher IOERT dose (≥ 12.5 Gy; HR 0.32, p = 0.02) retained a significant association in multivariate analysis. CONCLUSION: From this joint analysis emerges the fact that an IOERT dose ≥ 12.5 Gy increases the rate of IOERT in-field control, but DFS remains modest, given the high risk of distant metastases. Intensified local treatment needs to be tested in the context of more efficient concurrent, neo- and adjuvant systemic therapy.

Intraoperative radiation therapy, opportunities for clinical practice normalization: MEDTING, a scientific platform.

AIM: To use a platform to analyze a subgroup specialized in evaluation of patients candidates to IOERT. BACKGROUND: Medting is a project that was initiated to support daily clinical activity, knowledge management and medical education by sharing information with other physicians. The project began at the "Hospital General Universitario Gregorio Marañón", which has a dedicated oncology physician's multi-specialist committee. There are many scientific social networks all over the world. Medting is the only platform that specializes in healthcare and has been developed for hospital purposes. MATERIALS AND METHODS: Medting brings all together the relevant clinical information from electronic medical records and picture archiving about the patient to study. Subplatform Medting-IORT was created on February 2, 2012 at the Hospital General Universitario Gregorio Marañon. It has 23 members, have been registered 18 cases with 238 multimedia images. RESULTS: Medting started with 28 physicians and five departments. After 6 months, proof of concept period, there are 225 physicians, more than 120 medical students and 39 departments in 3 hospitals using the scientific social network. Furthermore, the project is being extended on three more hospitals in Madrid. CONCLUSION: Medting gives the opportunity to oncology physicians to access all relevant clinical information with the ability to discuss case notes and view images at any time. The impact of the Medting platform in a subgroup working team to evaluate IOERT patients candidates is included in the analysis. The use of a constantly updated repository based on real cases and the documentation of the internal activity of the tumor committee beyond the medical record, has become an extraordinary tool for teaching, training and learning.

Intraoperative radiation therapy opportunities for clinical practice normalization: Data recording and innovative development.

BACKGROUND: Intraoperative radiotherapy (IORT) refers to the delivery of a high dose of radiation at the time of surgery. AIM: To analyze clinical and research-oriented innovative activities developed in a 17-year period using intraoperative electron-radiation therapy (IOeRT) as a component of treatment in a multidisciplinary approach for cancer management. MATERIALS AND METHODS: From 01/1995 to 03/2012 IOeRT procedures were registered in a specific Hospital-based database. Research and developments in imaging and recording for treatment planning implementation are active since 2006. RESULTS: 1004 patients were treated and 1036 IORT procedures completed. Median age of patients was 61 (range 5 months to 94 years). Gender distribution was male in 54% of cases and female in 46%. Disease status at the time of IORT was 796 (77%) primary and 240 (23%) recurrent. Cancer type distribution included: 62% gastrointestinal, 18% sarcoma, 5% pancreas, 2% paediatric, 3% breast, 77 7% oligotopic recurrences, 2% other. IORT technical characteristics were: Applicator size 5 cm 22%, 6 cm 21%, 7 cm 21%, 8 cm 15%, 9 cm 6%, 10 cm 7% 12 cm 5% 15 cm 3%. Electron energies: 6 MeV 19%, 8 MeV 15%, 10 MeV 15%, 12 MeV 23%, 15 MeV 19%, 18 MeV 6%, other 3%. Multiple fields: 108 (11%). Dose: 7.5 Gy 3%, 10 Gy 35%, 12 Gy 3%, 12.5 Gy 49%, 15 Gy 5%, other 5%. CONCLUSION: An IORT programme developed in an Academic Hospital based on practice-oriented medical decisions is an attractive interdisciplinary oncology initiative proven to be able to generate an intensive clinical activity for cancer patient quality care and a competitive source of scientific patient-oriented research, development and innovation.

Postchemoradiation resected locally advanced esophageal and gastroesophageal junction carcinoma: long-term outcome with or without intraoperative radiotherapy.

BACKGROUND: To report feasibility, tolerance, anatomical topography of locoregional recurrence (LRR), and long-term outcome for esophageal and esophagogastric (EG) cancer patients treated with preoperative chemoradiation (CRT) and surgery with or without a radiation boost of intraoperative electron beam radiotherapy (IOERT). METHODS: From January 1995 to December 2010, 53 patients with primary esophageal (n = 26; 44 %) or EG carcinoma (n = 30; 56 %), and disease confined to locoregional area [clinical stage: IIb (n = 30; 57 %), IIIa (n = 14; 26 %), IIIb (n = 6; 11 %), IIIc (n = 3; 6 %)], were treated with preoperative CRT, curative (R0) resection with an extended (two-field) lymph node dissection in all cases. Thirty-seven patients also received a preanastomotic reconstruction IOERT boost (applicator diameter size 6-9 cm, dose 10-15 Gy, beam energy 6-15 MeV) over the tumor bed in the mediastinum and upper abdominal lymph node area. RESULTS: With a median follow-up time of 27.9 months (range, 0.2-148), LRR rate was 15 % (n = 8). Five-year overall survival (OS) and disease-free survival was 48 and 36 %, respectively. Univariate log-rank analyses showed that receiving IOERT was associated with lower risk of LRR (p = 0.004). On multivariate analysis, only the IOERT group retained significance in relation to LRR (odds ratio, 0.08; 95 % confidence interval, 0.01-0.48; p = 0.01). Postoperative mortality and perioperative complications were 11 % (n = 6) and 30 % (n = 16). CONCLUSIONS: Local control is high in the radiation-boosted area, but OS remains modest, given the high risk of distant metastases. Intensified locoregional treatment needs to be tested in the context of more efficient concurrent, neo-, and adjuvant systemic therapy.

¹8F-FDG PET/CT-based treatment response evaluation in locally advanced rectal cancer: a prospective validation of long-term outcomes.

PURPOSE: To prospectively evaluate the usefulness of (18)F-FDG PET/CT) imaging for predicting histopathological response and long-term clinical outcomes in locally advanced rectal cancer (LARC). METHODS: This prospective study included 38 patients with a confirmed diagnosis of LARC (cT3-4 or cN+) who underwent (18)F-FDG PET/CT before and after neoadjuvant therapy (NAT). Total mesorectal excision was scheduled 6 weeks after NAT and was followed by an expert histopathological analysis of the surgical specimen. Baseline variables and previously identified maximum FDG standardized uptake value (SUVmax) cut-off values before NAT (SUVmaxPRE ≥6) and after NAT (SUVmaxPOST ≥2), and the absolute and percentage reductions from baseline SUVmax (∆SUVmax <4 and ∆SUVmax% <65 %, respectively) were applied to differentiate patients showing a metabolic tumour response from nonresponders. These features were correlated with tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS). RESULTS: Significantly higher 5-year DFS and OS were seen in 19 responders (TRG 3 or 4) than in 19 nonresponders (TRG 0-2; 94.4 vs. 48.8 %, p = 0.001; 94.7 vs. 63.2 %, p = 0.02, respectively). In multivariate analysis the only PET/CT SUVmax-based parameter significantly correlated with the likelihood of recurrence and survival was ∆SUV% <65 % (HR = 5.95, p = 0.02, for DFS; HR = 5.26, p = 0.04, for OS) CONCLUSION: This prospective study proved that (18)F-FDG PET/CT is a valuable imaging tool for assessing rectal cancer TRG and long-term prognosis, and could potentially serve as an intermediate endpoint in treatment optimization research and rectal cancer patient care.

Clinical significance of VEGFR-2 and ¹8F-FDG PET/CT SUVmax pretreatment score in predicting the long-term outcome of patients with locally advanced rectal cancer treated with neoadjuvant therapy.

PURPOSE: Vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor-1 (EGFR), and cyclooxygenase-2 (COX-2) stimulate key processes involved in tumor progression and are important targets for cancer drugs. (18)F-FDG maximum standardized uptake value (SUVmax) is a marker of tumor metabolic activity. The purpose of this study was to measure SUVmax combined with VEGFR-2, EGFR and COX-2 proteins in pretreatment tumor biopsies from patients with locally advanced rectal cancer receiving intensive neoadjuvant treatment and to correlate the findings with clinical outcome. METHODS: VEGFR-2, EGFR and COX-2 were measured using the immunoreactive score (IRS). SUVmax (median 8.4) was quantified in tumors with molecular overexpression (IRS ≥3 + SUVmax ≥ 8.4 indicating active tumors; SUVmax <8.4 indicating inactive tumors). The Cox proportional hazards model was used to explore associations between tumor markers, disease-free survival (DFS) and overall survival (OS). RESULTS: The study group comprised 38 patients with a median follow-up of 69.3 months (range 4.5 - 92 months). Multivariate analysis showed that active tumors (overexpressing VEGFR-2, high SUVmax) were associated with worse DFS (HR 4.73, 95 % CI 1.18 - 22.17; p = 0.04) and OS (HR 4.28, 95 % CI 1.04 - 20.12; p = 0.05). CONCLUSION: Active tumors overexpressing VEGFR-2 are associated with a worse overall outcome in patients with rectal cancer treated with induction chemotherapy followed by pelvic chemoradiation and surgery. The optimal diagnostic cut-off level for this novel biomarker association should be investigated. Evaluation in a clinical trial is required to determine whether selected patients could benefit from a VEGFR-targeting drug.

Chemoradiation for resected pancreatic adenocarcinoma with or without intraoperative radiation therapy boost: Long-term outcomes.

BACKGROUND/OBJECTIVES: To analyze prognostic factors associated with long-term outcomes in patients with pancreatic cancer treated with chemoradiation therapy (CRT) and surgery with or without intraoperative electron beam radiotherapy (IOERT). PATIENTS AND METHODS: From January 1995 to December 2012, 60 patients with adenocarcinoma of the pancreas and locoregional disease (clinical stage IB [n = 13; 22%], IIA [n = 16; 27%], IIB [n = 22; 36%], IIIC [n = 9; 15%]) were treated with CRT (45-50.4 Gy before surgery [n = 19; 32%] and after surgery [n = 41; 68%]) and curative resection (R0 [n = 34; 57%], R1 [n = 26, 43%]). Twenty-nine patients (48%) also received a pre-anastomosis IOERT boost (applicator diameter size, 7-10 cm; dose, 10-15 Gy; beam energy, 9-18 MeV). RESULTS: With a median follow-up of 15.9 months (range, 1-182), 5-year overall survival (OS), disease-free survival (DFS), and locoregional control were 20%, 13%, and 58%, respectively. Univariate analyses showed that R1 margin resection status (HR, 3.17; p = 0.04), not receiving IOERT (HR, 7.33; p = 0.01), and postoperative CRT (HR, 5.12; p = 0.04) were associated with a higher risk of locoregional recurrence. In the multivariate analysis, only margin resection status (HR, 3.0; p = 0.05) and not receiving IOERT (HR, 6.75; p = 0.01) retained significance with regard to locoregional recurrence. Postoperative mortality and perioperative complications were 3% (n = 2) and 43% (n = 26). CONCLUSIONS: Although local control is good in the radiation-boosted area, OS remains modest owing to high risk of distant metastases. Intensified locoregional treatment needs to be tested in the context of more efficient systemic therapy.

Undergraduate cancer education in Spain: The debate, the opportunities and the initiatives of the University Forum of the Spanish Society of Radiation Oncology (SEOR).

Most medical schools in Spain (80%) offer undergraduate training in oncology. This education is highly variable in terms of content (theory and practical training), number of credits, and the medical specialty and departmental affiliation of the professors. Much of this variability is due to university traditions in the configuration of credits and programmes, and also to the structure of the hospital-based practical training. Undergraduate medical students deserve a more coherent and modern approach to education with a strong emphasis on clinical practice. Oncology is an interdisciplinary science that requires the input of professors from multiple specialties to provide the primary body of knowledge and skills needed to obtain both a theoretical and clinical understanding of cancer. Clinical skills should be a key focus due to their importance in the current model of integrated medical management and care. Clinical radiation oncology is a traditional and comprehensive hospital-based platform for undergraduate education in oncology. In Spain, a significant number (n = 80) of radiation oncology specialists have a contractual relationship to teach university courses. Most Spanish universities (80%) have a radiation oncologist on staff, some of whom are department chairs and many others are full professors who have been hired and promoted under competitive conditions of evaluation as established by the National Agency for Quality Evaluation. The Spanish Society of Radiation Oncology (SEOR) has identified new opportunities to improve undergraduate education in oncology. In this article, we discuss proposals related to theoretical (20 items) and practical clinical training (9 items). We also describe the SEOR University Forum, which is an initiative to develop a strategic plan to implement and organize cancer education at the undergraduate level in an interdisciplinary teaching spirit and with a strong contribution from radiation oncologists.