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Background: Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individuallevel surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial. Patients and methods: Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. Results: After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P=0.034; PC 1) and resulted in a shift toward lower NAR groups (P=0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P<0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106-7.020; P<0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P=0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4. Conclusion: Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy. [ABSTRACT FROM AUTHOR]

Abstract Aim The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy (RCT) is recommended for advanced disease (pT3/4 or pN+). In recent years, encouraging results of pre-operative radiotherapy have been reported. This prospective randomized phase-III-trial (CAO/ARO/AIO-94) compares the efficacy of neoadjuvant RCT to standard postoperative RCT. We report on the design of the study and first results with regard to toxicity of RCT and postoperative morbidity. Patients and methods Patients with locally advanced operable rectal cancer (uT3/4 or uN+, Mason CS III/IV) were randomly assigned to pre or postoperative RCT: A total dose of 50.4 Gy (single dose 1.8 Gy) was applied to the tumour and the pelvic lymph nodes. 5-FU (1000 mg/m2 /d) was administered concomitantly in the 1th and 5th week of radiation as 120 h-continuous infusion. Four additional cycles of 5-FU-chemotherapy (500 mg/m2 /d, i.v.-bolus) were applied. RCT was identical in both arms except for a small-volume boost of 5.4 Gy postoperatively. The time interval between RCT and surgery was 4–6 weeks in both arms. Techniques of surgery were standardized and included total mesorectal excision. Primary endpoints of the study are 5-year survival and local and distant control. Secondary endpoints include the rate of curative (R0) resection and sphincter saving procedures, toxicity of RCT, surgical complications and quality of life. Results As of July 2002, 805 patients were randomized from 26 participating institutions. Acute toxicity (WHO) of RCT was low, with less than 15% of patients experiencing grade 3 or higher toxicity: The principal toxicity was diarrhea, with 12% in the postoperative RCT-arm and 11% in the pre-operative RCT-arm having grade 3-, and 1% in either arm having grade 4-diarrhea. Erythema, nausea and leukopenia were the next common toxicities, with less than 3% of patients in either arm suffering grade 3 or greater leukopenia or nausea. Postoperative complication rates were similar in both arms, with 12% (postop. RCT) and 12% (pre-op. RCT) of patients, respectively, suffering from anastomotic leakage, 3% (postop. RCT) and 3% (pre-op. RCT) from postoperative bleeding, and 6% (postop. RCT) and 4% (pre-op. RCT) from delayed wound healing. Conclusion The patient accrual to the trial is satisfactory. Neoadjuvant RCT is well tolerated and bears no higher risk for postoperative morbidity. [ABSTRACT FROM AUTHOR]

Neutrophils are known to contribute in many aspects of tumor progression and metastasis. The presence of neutrophils or neutrophil-derived mediators in the tumor microenvironment has been associated with poor prognosis in several types of solid tumors. However, the effects of classical cancer treatments such as radiation therapy on neutrophils are poorly understood. Furthermore, the cellular composition and distribution of immune cells in the tumor is of increasing interest in cancer research and new imaging technologies allow to perform more complex spatial analyses within tumor tissues. Therefore, we aim to offer novel insight into intra-tumoral formation of cellular neighborhoods and communities in murine breast cancer. To address this question, we performed image mass cytometry on tumors of the TS/A breast cancer tumor model, performed spatial neighborhood analyses of the tumor microenvironment and quantified neutrophil-extracellular trap degradation products in serum of the mice. We show that irradiation with 2 × 8 Gy significantly alters the cellular composition and spatial organization in the tumor, especially regarding neutrophils and other cells of the myeloid lineage. Locally applied radiotherapy further affects neutrophils in a systemic manner by decreasing the serum neutrophil extracellular trap concentrations which correlates positively with survival. In addition, the intercellular cohesion is maintained due to radiotherapy as shown by E-Cadherin expression. Radiotherapy, therefore, might affect the epithelial–mesenchymal plasticity in tumors and thus prevent metastasis. Our findings underscore the growing importance of the spatial organization of the tumor microenvironment, particularly with respect to radiotherapy, and provide insight into potential mechanisms by which radiotherapy affects epithelial–mesenchymal plasticity and tumor metastasis. [ABSTRACT FROM AUTHOR]

A response by the authors to a comment by Dr S. Papagrigoriadis on their article "Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a phase I/II study," published in Vol. 94 of this journal is presented.

Radiotherapy (RT) is a standard treatment for indolent, primary cutaneous B-cell lymphoma. As various RT-concepts exist comprising different doses, fractionations and techniques, a multicenter registry was established to investigate patterns-of-care, response outcomes, and to guide treatment decisions. The analysis included patients with stage T1/T2 primary cutaneous B-cell lymphoma, either as primary cutaneous marginal zone lymphoma (PCMZL) or primary cutaneous follicle center lymphoma (PCFCL), who underwent RT between 2000 and 2020. Data from twenty participating institutions were collected in a data collection web application database (Vanderbilt University, TN, USA) and analyzed via statistical software. Overall, 440 patients were included, of which 60.9 % were male with a median age of 56.8 years at diagnosis. Histologically, 37.3 % had PCMZL and 54.1 % had PCFCL. A median of 1 lesion (range = 1-10) with a median size of 2.9 cm (range = 0.1-21 cm) were reported. Previous therapies were delivered in 40.9 % of patients with a complete resection in 8.2 %. RT doses differed between 2.0 and 50.4 Gy (Median = 24.0 Gy) with a median fraction dose of 2.0 Gy (1.5-5.0 Gy). Of these, 51 patients were treated with 4 Gy or less. Overall response rate (ORR) at first follow-up was 77.8 % with a complete response rate (CRR) of 76.4 %, reaching a best response of 95.6 % (CRR: 92 %) after a median of 3.9 months. There was a significant difference in OR and CR between the < = 4 Gy and > 4 Gy groups, respectively (ORR = 90.2 % vs. 97.4 %; P = 0.022; CRR = 82.4 % vs. 94.3 %; P = 0.005). Erythema only developed after RT >4 Gy (50.5 % of patients with documented values vs. 0.0 %; P < 0.001), although grades were predominantly mild to moderate (45.2 % grade 1, 4.6 % grade 2 in the > 4 Gy group). There was a significant difference in freedom from local failure between the ≤ 4 Gy group and patients treated with higher doses (5-year freedom from local failure: 71.8 % vs. 95.4 %; P < 0.001), with no difference in overall survival (5-year overall survival 97.1 % vs. 93.7 % P = 0.290). RT is an effective treatment modality for indolent, primary cutaneous B-cell lymphoma. As very low doses (e.g., 4 Gy) led to long-term disease control in ca. 70 % of patients, a response-adapted approach could be further explored with full-dose salvage RT being applied in case of a local failure after 4 Gy. Patient recruitment is still ongoing and final results are to be expected at the ASTRO meeting. [ABSTRACT FROM AUTHOR]

In most institutions neoadjuvant chemoradiation for middle and lower rectal carcinoma is currently given to patients with tumours of clinical stages II or III (cT3,4 and/or N1,2). The possibility of a reduction in the use of neoadjuvant chemoradiation by an individualized magnetic resonance imaging (MRI)-based indication for neoadjuvant chemoradiation was analysed. Assessment of the pathological and oncological principles indicating for neoadjuvant treatment was used to determine the prognostic importance of the distance between the tumour and the circumferential resection margin and pretherapeutic assessment using modern MRI. Based on the results of pretreatment MRI scanning, a proposal is presented for the treatment of middle and lower rectal carcinoma with neoadjuvant chemoradiation. Adopting this proposal, the frequency of neoadjuvant chemoradiation decreased from 70% to 35% and the early and late adverse effects of this therapy were reduced. In contrast, the expected locoregional recurrence rate increased from 6% to 11% if all quality criteria were met and to 18% if not. An MRI-based indication for neoadjuvant chemoradiation is justified only for centres with regular quality assurance of MRI, surgery, radiotherapy and pathology. The proposal needs confirmation by long-term follow up and by prospective studies with larger numbers of patients. [ABSTRACT FROM AUTHOR]

Poster: RTT track: Image guided radiotherapy and verification protocols PO-1904: ROI optimisation for surface guided radiation therapy T. Sauer, D. Popp, R. Fietkau, C. Bert. [Extracted from the article]

The combination of cisplatin, 5-fluorouracil (5-FU) and cetuximab (PFC) is the reference first-line treatment for recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). We analysed whether treatment intensification by the addition of docetaxel to PFC improved efficacy in R/M SCCHN. A total of 180 patients with R/M SCCHN (1:1) were assigned to receive either cisplatin (40 mg/m2), docetaxel (40 mg/m2) and 5-FU (2000 mg/m2) at days 1 and 8 and cetuximab (400/250 mg/m2) at days 1, 8 and 15 (DPFC) or standard cisplatin (100 mg/m2) at day 1, 5-FU (1000 mg/m2) at days 1–4 and cetuximab (400/250 mg/m2) at days 1, 8 and 15 (PFC). Chemotherapy was repeated every 21 days and continued for a maximum of 6 cycles in absence of disease progression or limiting toxicity, followed by cetuximab maintenance (500 mg/m2 every 2 weeks). The primary end-point was progression-free survival (PFS). A preplanned interim analysis for toxicity after 20 patients/arm revealed excessive grade 3 and 4 gastrointestinal (65%) and infectious toxicities (35%) in arm A, which led to dose reduction of cisplatin to 30 mg/m2 and 5-FU to 1000 mg/m2 for subsequent patients. With a median follow-up of 2 years, grade 4 toxicities were 21.3% vs. 30.8% for DPFC and PFC, respectively. More treatment-related deaths occurred with DPFC vs. PFC, with 11.2% and 6.6%, respectively. For DPFC and PFC, the median PFS was 6.3 vs. 6.4 months (hazard ratio [HR] = 0.97, p = 0.87), the median overall survival was 8.9 vs. 10.6 months (HR = 1.29 p = 0.1) and response rates were 38.2% vs. 31.9% (p = 0.9), respectively. DPFC failed to improve efficacy in R/M SCCHN. On the contrary, a high toxicity and mortality rate was detected in both arms, which underscores the vulnerability of patients with R/M SCCHN, and research on the need for further optimisation of the front-line chemotherapy backbone is ongoing. • The CeFCiD trial was a randomized, multi-centre phase II trial to explore treatment intensification. • Within the trial population severe toxicities occurred. • Intensification of treatment schedule failed to improve survival. [ABSTRACT FROM AUTHOR]

Background: The influence of postoperative complications on survival in patients with locally advanced rectal cancer undergoing combined modality treatment is debatable. This study evaluated the impact of surgical complications on oncological outcomes in patients with locally advanced rectal cancer treated within the randomized CAO/ARO/AIO‐94 (Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society) trial. Methods: Patients were assigned randomly to either preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) or postoperative CRT between 1995 and 2002. Anastomotic leakage and wound healing disorders were evaluated prospectively, and their associations with overall survival, and distant metastasis and local recurrence rates after a long‐term follow‐up of more than 10 years were determined. Medical complications (such as cardiopulmonary events) were not analysed in this study. Results: A total of 799 patients were included in the analysis. Patients who had anterior or intersphincteric resection had better 10‐year overall survival than those treated with abdominoperineal resection (63·1 versus 51·3 per cent; P < 0·001). Anastomotic leakage was associated with worse 10‐year overall survival (51 versus 65·2 per cent; P = 0·020). Overall survival was reduced in patients with impaired wound healing (45·7 versus 62·2 per cent; P = 0·009). At 10 years after treatment, patients developing any surgical complication (anastomotic leakage and/or wound healing disorder) had impaired overall survival (46·6 versus 63·8 per cent; P < 0·001), a lower distant metastasis‐free survival rate (63·2 versus 72·0 per cent; P = 0·030) and more local recurrences (15·5 versus 6·4 per cent; P < 0·001). In a multivariable Cox regression model, lymph node metastases (P < 0·001) and surgical complications (P = 0·008) were the only independent predictors of reduced overall survival. Conclusion: Surgical complications were associated with adverse oncological outcomes in this trial. [ABSTRACT FROM AUTHOR]

Background The German rectal cancer trial CAO/ARO/AIO-04 has shown a significant benefit in 3-year disease-free survival (DFS) of adding oxaliplatin to a standard preoperative 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) and adjuvant chemotherapy in patients with locally advanced rectal cancer. The use of oxaliplatin as adjuvant treatment in elderly patients with colon cancer is controversial. We therefore investigated the impact of age on clinical outcome in the CAO/ARO/AIO-04 phase III trial. Patients and methods We carried out a post hoc analysis of the CAO/ARO/AIO-04 phase III trial evaluating primary and secondary end points according to age. Patient and tumor characteristics, NCI CTC adverse events grades 3–4 (version 3.0), dose intensities as well as survival and recurrence data were analyzed in three specified age groups (<60, 60–70, and ≥70 years). The influence of age as a continuous variable on DFS was modeled using a subpopulation treatment effect pattern plot (STEPP) analysis. Results A total of 1232 patients were assessable. With the exception of Eastern Cooperative Oncology Group status (P  <   0.001), no differences in patient and tumor characteristics were noticed between age groups. Likewise, toxicity pattern, dose intensities of CRT and surgical results were similar in all age groups. After a median follow-up of 50 months, in patients aged <60 years a significant benefit of adding oxaliplatin to 5-FU-based CRT and adjuvant chemotherapy was observed for local (P  =   0.013) and systemic recurrences (P  =   0.023), DFS (P  =   0.011), and even overall survival (OS; P  =   0.044). The STEPP analysis revealed improved hazard ratios for DFS in patients aged 40–70 years compared with elderly patients treated with oxaliplatin. Conclusion The addition of oxaliplatin significantly improved DFS and OS in younger patients aged <60 years with advanced rectal cancer. Patients aged ≥70 years had no benefit. Clinical Trials Number NCT00349076 [ABSTRACT FROM AUTHOR]

Purpose There is a sound theoretical basis but little clinical evidence substantiating the benefits of concurrent chemoradiotherapy with two-drug chemotherapy for locally advanced soft tissue sarcomas. Our five-year data on the feasibility and effectiveness of neoadjuvant chemoradiotherapy with systemically effective doses of adriamycin and ifosfamide combined is presented here. Patients and methods Between 2000 and 2011, 53 patients with UICC (2010) stage I ( n = 1, 1.9%), II ( n = 12, 22.7%) or III ( n = 40, 75.5%) nonmetastatic soft tissue sarcoma received neoadjuvant chemoradiotherapy with ifosfamide (1.5 g/m 2 /day, d1–5, q28) and doxorubicin (50 mg/m 2 /day, d3, q28) plus concurrent radiotherapy with a target dose of 50–64 Gy (median 60 Gy). The treatment of 34 patients (64.2%) was combined with hyperthermia. Results At five years, the local control rate was 89.9% (± 5.7%), distant metastasis-free survival 66.6% (± 7.6%), and survival 83.3% (± 6%). The R0 resection rate was 81.1%. Radiotherapy was completed as planned in all patients and chemotherapy in 42/53 (70.2%). Grades III ( n = 21, 29.6%) and IV ( n = 18, 34%) leukopenia was the main acute adverse event. All acute and chronic non-hematologic toxicities were moderate. Conclusion Neoadjuvant chemoradiotherapy for soft tissue sarcoma is associated with good feasibility, manageable acute and late toxicities, and high local efficacy. [ABSTRACT FROM AUTHOR]

Benign painful and inflammatory diseases have been treated for decades with low/moderate doses of ionizing radiation ( LD- X-irradiation). Tissue macrophages regulate initiation and resolution of inflammation by the secretion of cytokines and by acting as professional phagocytes. Having these pivotal functions, we were interested in how activated macrophages are modulated by LD- X-irradiation, also with regard to radiation protection issues and carcinogenesis. We set up an ex-vivo model in which lipopolysaccharide pre-activated peritoneal macrophages (p MΦ) of radiosensitive BALB/c mice, mimicking activated macrophages under inflammatory conditions, were exposed to X-irradiation from 0·01 Gy up to 2 Gy. Afterwards, the viability of the p MΦ, their transmigration and chemotaxis, the phagocytic behaviour, the secretion of inflammatory cytokines and underlying signalling pathways were determined. Exposure of p MΦ up to a single dose of 2 Gy did not influence their viability and phagocytic function, an important fact regarding radiation protection. However, significantly reduced migration, but increased chemotaxis of p MΦ after exposure to 0·1 or 0·5 Gy, was detected. Both might relate to the resolution of inflammation. Cytokine analyses revealed that, in particular, the moderate dose of 0·5 Gy applied in low-dose radiotherapy for inflammatory diseases results in an anti-inflammatory cytokine microenvironment of p MΦ, as the secretion of the proinflammatory cytokine interleukin ( IL)-1β was reduced and that of the anti-inflammatory cytokine transforming growth factor ( TGF)-β increased. Further, the reduced secretion of IL-1β correlated with reduced nuclear translocation of nuclear factor ( NF)-κ B p65, starting at exposure of p MΦ to 0·5 Gy of X-irradiation. We conclude that inflammation is modulated by LD- X-irradiation via changing the inflammatory phenotype of macrophages. [ABSTRACT FROM AUTHOR]

Background The subdivision of T3 in rectal carcinoma according to the depth of invasion into perirectal fat has been recommended in the TNM Supplement since 1993. This study assessed the prognostic impact of this pathological staging in tumours removed after neoadjuvant chemoradiotherapy ( ypT3). Methods Data from patients with ypT3 rectal carcinoma (less than 12 cm from the anal verge) treated with neoadjuvant chemoradiation and total mesorectal excision were analysed. Tumour category ypT3 was subdivided into ypT3a (5 mm or less) and ypT3b (more than 5 mm), based on histological measurements of maximal tumour invasion beyond the outer border of the muscularis propria. Results Important differences between ypT3a (81 patients) and ypT3b (43) were found in 5-year rates of locoregional recurrence (7 versus 18 per cent; P = 0·049), distant metastasis (20 versus 41 per cent; P = 0·002), disease-free survival (73 versus 47 per cent; P = 0·001), overall survival (79 versus 74 per cent; P = 0·036) and cancer-related survival (81 versus 74 per cent; P = 0·007). In Cox regression analyses, the ypT3 subclassification was identified as an independent prognostic factor for disease-free ( ypT3b: hazard ratio ( HR) 2·13, 95 per cent confidence interval 1·16 to 3·89; P = 0·014), observed ( ypT3b: HR 2·02, 1·05 to 3·87; P = 0·035) and cancer-related ( ypT3b: HR 2·46, 1·20 to 5·04; P = 0·014) survival. Extramural venous invasion was found to be an additional prognostic factor, but the pathological node category after chemoradiotherapy ( ypN) did not influence survival. Conclusion In ypT3 rectal carcinomas, the proposed subclassification is superior to ypN in predicting prognosis. [ABSTRACT FROM AUTHOR]

Summary: Head and neck squamous cell cancers (HNSSC) generate an immune-suppressive micro-environment by a specific pattern of tumour infiltrating inflammatory cells. The aim of our study was to evaluate the impact of radiochemotherapy on the numbers and composition of inflammatory cells and its influence on outcome. Fifty-eight patients suffering from oral cavity cancer were studied, whose therapy consisted of concurrent radiochemotherapy followed by surgery. Numbers and ratios of tumour infiltrating inflammatory cells were compared prior to and after radiochemotherapy. Intraepithelial and stromal location of tumour infiltrating inflammatory cells was analysed separately. Infiltration of CD3+, CD4+, CD25+, FoxP3+, CD8+, Granzyme B+, CD20+ and CD68+ cells predominated in the peritumoural stromal compartment, whereas CD1a+ dendritic cells were found more frequently in the intraepithelial compartment. Neoadjuvant treatment was associated with a general decrease of tumour infiltrating inflammatory cells in both compartments. The CD8+ and Granzyme B+ cytotoxic cells decreased only slightly after RCT. In contrast, the decrease of FoxP3+ regulatory T cells was more pronounced and the cytotoxic T-cell/FoxP3+ ratio increased 2- to 3-fold in both compartments, respectively. Patients with high cytotoxic cell numbers, high dendritic cell numbers and a high ratio of cytotoxic cells to regulatory T cells had a better disease free survival. Concurrent radiochemotherapy of oral squamous cell carcinoma was shown to drive the composition of inflammatory cells in a direction which is supposed to be prognostically favourable. [Copyright &y& Elsevier]

BACKGROUND: Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. METHODS: This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m(2) days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m(2) days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m(2) days 1 and 15), leucovorin (400 mg/m(2) days 1 and 15), and infusional fluorouracil (2400 mg/m(2) days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS: Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group. INTERPRETATION: Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. FUNDING: German Cancer Aid (Deutsche Krebshilfe). [ABSTRACT FROM AUTHOR]

Abstract: Background: Continuous hyperfractionated accelerated radiotherapy (CHART) counteracts repopulation and may significantly improve outcome of patients with non-small-cell lung cancer (NSCLC). Nevertheless high local failure rates call for radiation dose escalation. We report here the final results of the multicentric CHARTWEL trial (CHART weekend less, ARO 97-1). Patients and methods: Four hundred and six patients with NSCLC were stratified according to stage, histology, neoadjuvant chemotherapy and centre and were randomized to receive 3D-planned radiotherapy to 60Gy/40 fractions/2.5weeks (CHARTWEL) or 66Gy/33 fractions/6.5weeks (conventional fractionation, CF). Results: Overall survival (OS, primary endpoint) at 2, 3 and 5yr was not significantly different after CHARTWEL (31%, 22% and 11%) versus CF (32%, 18% and 7%; HR 0.92, 95% CI 0.75–1.13, p =0.43). Also local tumour control rates and distant metastases did not significantly differ. Acute dysphagia and radiological pneumonitis were more pronounced after CHARTWEL, without differences in clinical signs of pneumopathy. Exploratory analysis revealed a significant trend for improved LC after CHARTWEL versus CF with increasing UICC, T or N stage (p =0.006–0.025) and after neoadjuvant chemotherapy (HR 0.48, 0.26–0.89, p =0.019). Conclusions: Overall, outcome after CHARTWEL or CF was not different. The lower total dose in the CHARTWEL arm was compensated by the shorter overall treatment time, confirming a time factor for NSCLC. The higher efficacy of CHARTWEL versus CF in advanced stages and after chemotherapy provides a basis for further trials on treatment intensification for locally advanced NSCLC. [Copyright &y& Elsevier]

Most of the classical therapies for solid tumors have limitations in achieving long-lasting anti-tumor responses. Therefore, treatment of cancer requires additional and multimodal therapeutic strategies. One option is based on the vaccination of cancer patients with autologous inactivated intact tumor cells. The master requirements of cell-based therapeutic tumor vaccines are the: (a) complete inactivation of the tumor cells; (b) preservation of their immunogenicity; and (c) need to remain in accordance with statutory provisions. Physical treatments like freeze-thawing and chemotherapeutics are currently used to inactivate tumor cells for vaccination purposes, but these techniques have methodological, therapeutic, or legal restrictions. For this reason, we have proposed the use of a high hydrostatic pressure (HHP) treatment ( p ≥ 100 MPa) as an alternative method for the inactivation of tumor cells. HHP is a technique that has been known for more than 100 years to successfully inactivate micro-organisms and to alter biomolecules. In the studies here, we show that the treatment of MCF7, B16-F10, and CT26 tumor cells with HHP ≥ 300 MPa results in mainly necrotic tumor cell death forms displaying degraded DNA. Only CT26 cells yielded a notable amount of apoptotic cells after the application of HHP. All tumor cells treated with ≥ 200 MPa lost their ability to form colonies in vitro. Furthermore, the pressure-inactivated cells retained their immunogenicity, as tested in a xenogeneic as well as syngeneic mouse models. We conclude that the complete tumor cell inactivation, the degradation of the cell’s nuclei, and the retention of the immunogeneic potential of these dead tumor cells induced by HHP favor the use of this technique as a powerful and low-cost technique for the inactivation of tumor cells to be used as a vaccine. [ABSTRACT FROM AUTHOR]

Background: No standard treatment for locally advanced pancreatic cancer (LAPC) is defined.Patients and Methods: Within a multi-centre, randomised phase II trial, 95 patients with LAPC were assigned to three different chemoradiotherapy (CRT) regimens: patients received conventionally fractionated radiotherapy of 50 Gy and were randomised to concurrent 5-fluorouracil (350 mg m(-2) per day on each day of radiotherapy, RT-5-FU arm), concurrent gemcitabine (300 mg m(-2)), and cisplatin (30 mg m(-2)) on days 1, 8, 22, and 29 (RT-GC arm), or the same concurrent treatment followed by sequential full-dose gemcitabine (1000 mg m(-2)) and cisplatin (50 mg m(-2)) every 2 weeks (RT-GC+GC arm). Primary end point was the overall survival (OS) rate after 9 months.Results: The 9-month OS rate was 58% in the RT-5-FU arm, 52% in the RT-GC arm, and 45% in the RT-GC+GC arm. Corresponding median survival times were 9.6, 9.3, and 7.3 months (P=0.61) respectively. The intent-to-treat response rate was 19, 22, and 13% respectively. Median progression-free survival was estimated with 4.0, 5.6, and 6.0 months (P=0.21). Grade 3/4 haematological toxicities were more frequent in the two GC-containing arms, no grade 3/4 febrile neutropaenia was observed.Conclusion: None of the three CRT regimens tested met the investigators' definition for efficacy; the median OS was similar to those previously reported with gemcitabine alone in LAPC. [ABSTRACT FROM AUTHOR]

Abstract: Standard treatment for muscle-invasive bladder cancer is cystectomy. Multimodality treatment, including transurethral resection of the bladder tumour, radiation therapy, chemotherapy and deep regional hyperthermia, has been shown to produce survival rates comparable with those of cystectomy. With these programmes, cystectomy has been reserved for patients with incomplete response or local relapse. During the past two decades, organ preservation by multimodality treatment has been investigated in prospective series from single centres and co-operative groups, with more than 1000 patients included. Five-year overall survival rates in the range of 50–60% have been reported, and about three-quarters of the surviving patients maintained their bladder. Clinical criteria helpful in determining patients for bladder preservation include such variables as small tumour size (<5cm), early tumour stage, a visibly and microscopically complete transurethral resection, absence of ureteral obstruction, and no evidence of pelvic lymph node metastases. On multivariate analysis, the completeness of transurethral resection of a bladder tumour was found to be one of the strongest prognostic factors for overall survival. Patients at greater risk of new tumour development after initial complete response are those with multifocal disease and extensive associated carcinoma in situ at presentation. Close co-ordination among all disciplines is required to achieve optimal results. Future investigations will focus on optimising radiation techniques, including all possibilities of radiosensitisation (e.g. concurrent radiochemotherapy, deep regional hyperthermia), and incorporating more effective systemic chemotherapy, and the proper selection of patients based on predictive molecular makers. [Copyright &y& Elsevier]

Abstract: Background: Extracorporeal photopheresis is a therapy for treatment of autoimmune diseases, cutaneous T-cell lymphoma, organ graft rejection as well as graft-versus-host diseases. The exact mechanism how the combination of 8-methoxypsoralen plus UV-A irradiation (PUVA) acts is still unclear. We investigated the cell death of activated and non-activated lymphocytes after PUVA treatment as well as the rate of released blebs and their antigen composition. Results: In presence of 8-MOP, UV-A light highly significantly increased the cell death of activated lymphocytes. The same was observed to a lesser extent in non-activated cells. Blebs derived from activated lymphocytes after PUVA treatment showed the highest surface exposition of phosphatidylserine. These blebs also displayed a high exposure of the antigens CD5 and CD8 as well as a low exposure of CD28 and CD86. Conclusion: PUVA treatment exerts anti-inflammatory effects by inducing apoptosis and apoptotic cell-derived blebs with immune suppressive surface composition. [Copyright &y& Elsevier]

Purpose: CD4+CD25+FoxP3+ regulatory T-cells (Treg) are responsible for immunoevasion mechanisms induced by cancer. Specific chemokines such as CCL22 are presumed to mediate active Treg trafficking into the tumour site. In this context, the effects of irradiation and hyperthermia of tumour cells on Treg migration and the CCL22 concentration in the tumour cell supernatants after treatment were studied. Moreover, the relationship between CCL22 concentration and Treg cell migration was also examined. Materials and methods: Treg and CD4+CD25- T-cells were isolated from human peripheral blood. Supernatants were obtained from primary cell cultures derived from head and neck carcinoma patients. Tumour cell cultures were treated with a dose of 2 Gy and hyperthermia (41.5°C) or with hyperthermia or irradiation alone. Cancer cell culture supernatants were then used for a transmigration assay. Results: Treg and CD4+CD25- T-cells showed an increased transmigration towards supernatants of hyperthermia-treated tumour cells. After combined application of hyperthermia and irradiation, Treg migration was similar to control levels, but CD4+CD25- migration was still enhanced. Irradiation caused a significantly decreased Treg influx, whereas the CD4+CD25- T-cell migration was not altered after the same treatment. Changes of Treg chemotaxis could be attributed to a treatment-associated escalation of the CCL22 in the tumour cell supernatants. Conclusion: The combination of irradiation and hyperthermia is able to modify transmigration of tumour infiltrating lymphocytes beneficially and individually. In this in vitro system hyperthermia alone negatively impacts the immune response by selectively recruiting Treg, whereas hyperthermia with the addition of irradiation negates this effect. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) are often characterized by cellular as well as humoral deficiencies in the recognition and phagocytosis of dead and dying cells. The aim of this study was to investigate whether the remnants of apoptotic cells are involved in the induction of inflammatory cytokines in blood-borne phagocytes. METHODS: We used ex vivo phagocytosis assays comprising cellular and humoral components and phagocytosis assays with isolated granulocytes and monocytes to study the phagocytosis of secondarily necrotic cell-derived material (SNEC). Cytokines were measured by multiplex bead array technology. RESULTS: We confirmed the impaired uptake of various particulate targets, including immunoglobulin-opsonized beads, by granulocytes and monocytes from patients with SLE compared with healthy control subjects. Surprisingly, blood-borne phagocytes from two-thirds of the patients with SLE took up SNEC, which was rarely phagocytosed by phagocytes from healthy control subjects or patients with rheumatoid arthritis. Supplementation of healthy donor blood with IgG fractions derived from patients with SLE transferred the capability to take up SNEC to the phagocytes of healthy donors. Phagocytosis-promoting immune globulins also induced secretion of huge amounts of cytokines by blood-borne phagocytes following uptake of SNEC. CONCLUSION: Opsonization of SNEC by autoantibodies from patients with SLE fosters its uptake by blood-borne monocytes and granulocytes. Autoantibody-mediated phagocytosis of SNEC is accompanied by secretion of inflammatory cytokines, fueling the inflammation that contributes to the perpetuation of autoimmunity in SLE. [ABSTRACT FROM AUTHOR]

Brain metastases represent an important cause of morbidity in patients with lung cancer and are associated with a mean survival of less than 6 months. Thus, new regimens improving the outcome of these patients are urgently needed. On the basis of promising data raised in a phase I/II trial, we initiated an open, randomised, prospective, multicentric phase III trial, comparing whole brain radiation therapy (WBRT; 20 × 2 Gy) alone with WBRT+topotecan (RCT; 0.4 mg m−2 day−1 × 20). A total of 320 patients with CNS-metastases due to SCLC or NSCLC were projected. The primary end point was overall survival, whereas second end points were local response and progression-free survival. However, until the cutoff date of study completion (i.e., a study duration of 34 months), only a total of 96 (RCT:47, WBRT:49) patients had been recruited, and so an analysis was performed at that time point. Although the numbers of grade 3/4 non-haematological toxicities (besides alopecia 115 (RCT/WBRT: 55 out of 60) were evenly distributed, the 25 haematological events occurred mainly in the combined treatment arm (24 out of 1). Local response, evaluated 2 weeks after treatment, was assessable in 44 (RCT/WBRT: 23 out of 21) patients, showing CR in eight (3 out of 5), PR in 17 (11 out of 6), SD in 14 (8 out of 6) and PD in five (1 out of 4) patients (all differences n.s.). Neither OAS (RCT/WBRT: median (days)): 87 out of 95, range 3–752/4–433; HR 1.32; 95% CI (0.83; 2.10)) nor PFS (median (days)): 71 out of 66, range, 3–399/4–228; HR 1.28, 95% CI (0.73; 2.43) differed significantly. On the basis of these results and the slow recruitment, a continuation of the study did not seem reasonable. The available data show no significant advantage for concurrent radiochemotherapy for patients with lung cancer; however, the recruited number of patients is too low to exhibit a small advantage of combined treatment.British Journal of Cancer (2009) 100, 291–297. doi:10.1038/sj.bjc.6604835 www.bjcancer.com Published online 6 January 2009 [ABSTRACT FROM AUTHOR]

Reduced nutritional state is aßociated with unfavourable outcomes and a lower quality of life in patients with malignancies. Patients with active tumour disease frequently have insufficient food intake. The resting energy expenditure in cancer patients can be increased, decreased, or remain unchanged compared to predicted values. Tumours may result in varying degrees of systemic pro-inflammatory proceßes with secondary effects on all significant metabolic pathways. Therapeutic objectives are to stabilise nutritional state with oral/enteral nutrition and parenteral nutrition (PN) and thus to prevent or reduce progreßive weight loß. The maintenance or improvement of quality of life, and the increase in the effectiveneß and a reduction in the side-effects of antitumor therapy are further objectives. Indications for PN in tumour patients are eßentially identical to those in patients with benign ill illneßes, with preference given to oral or enteral nutrition when feasible. A combined nutritional concept is preferred if oral or enteral nutrition are poßible but not sufficient. There are generally no accepted standards for ideal energy and nutrient intakes in oncological patients, particularly when exclusive artificial nutrition is administered. The use of PN as a general accompaniment to radiotherapy or chemotherapy is not indicated, but PN is indicated in chronic severe radiogenic enteritis or after allogenic transplantation with pronounced mucositis or GvH- related gastrointestinal damage for prolonged periods, with particular Tumour Biology Center, attention to increased risk of bleeding and infection. No PN is neceßary in the terminal phase. [ABSTRACT FROM AUTHOR]

Poster: Physics track: Imaging acquisition and processing PO-1750: Comparison of MRI coils and RT-positioning systems for optimal MRI scanning in SRS cases V. Mengling, R. Perrin, F. Putz, R. Fietkau, C. Bert. [Extracted from the article]

Poster discussion: CL: CNS PD-0170: Volumetric regression in brain metastases after stereotactic RT: Time course and significance F. Putz, D. Oft, R. Perrin, V. Mengling, T. Weissmann, J. Roesch, S. Mansoorian, L. Distel, C. Bert, R. Fietkau. [Extracted from the article]

The aim of this study was to investigate the efficacy and safety of chemoradiation using capecitabine and irinotecan as neoadjuvant therapy for patients with rectal cancer. Conventional radiation was given at daily fractions of 1.8 Gy on 5 days a week for a total dose of 55.8 (50.4 + 5.4) Gy. Concurrently, irinotecan 40 mg m(-2) once weekly and capecitabine continuously at dose levels of 500, 650, 750 and 825 mg m(-2) twice daily were administered. Surgery was performed 4-6 weeks following completion of chemoradiation. A total of 28 patients (3 UICC II, 25 UICC III) were enrolled and all received treatment. Dose-limiting toxicity was diarrhoea grade IV and hand-foot syndrome at the 825 mg m(-2) dose level. The maximum tolerated dose of capecitabine was 750 mg m(-2). Diarrhoea was the most common toxicity: grade III in nine patients. Two patients died, one due to pneumonia and one due to sudden cardiac death. A complete response and only microfocal residual tumour disease was achieved in four and three patients (27%). In all, 25 of 28 patients undergoing surgery, 24 (96%) had R0 resection. Preoperative chemoradiation based on continuous daily capecitabine and weekly irinotecan appears to tolerated and effective in patients with rectal cancer. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy intensified with irinotecan in patients with locally advanced rectal cancer. Eligible patients had nonmetastatic disease at a locally advanced stage that made R0 resection and sphincter preservation uncertain. They received preoperative radiation over 6 weeks to 45 Gy and boost of 5.4 Gy and concurrent continuous infusion 5-fluorouracil 250 mg m(-2) day(-1) and weekly irinotecan 40 mg m(-2). In all, 37 patients entered the study. T stage at baseline as determined by ultrasound was T2/T3/T4 in 2/19/16 patients; 31 patients had lymph node involvement. The predominant toxicity was diarrhoea (grade 3/4 in 10/2 patients). Haematologic toxicity and surgical complications were moderate. Among 36 patients undergoing surgery, 32 (89%) had R0 resection and 23 (64%) sphincter preservation. Pathologic complete response (pCR) was achieved in eight (22%) of 36 patients, and 10 patients (28%) had only microscopic residual disease. At 4 years, overall survival was 66%, disease-free survival 73%, local relapse rate 7%, and distant failure rate 24%. Extent of resection and postoperative nodal status were significant predictors of overall and disease-free survival. Intensified neoadjuvant chemoradiotherapy with irinotecan can be safely administered and results in a high pCR rate. [ABSTRACT FROM AUTHOR]