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Background and purpose Tumour infiltrating lymphocytes (TIL) and tumour associated macrophages (TAM) play a key role in anticancer immunosurveillance. We studied their influence on response to neoadjuvant radiochemotherapy (RCT) and prognosis in patients with oesophageal adenocarcinoma (OAC). Materials and methods Between 10/2004 and 06/2018, pre-RCT biopsy-specimens were available from 76 patients with locally advanced, non-metastatic OAC scheduled for trimodality therapy. We evaluated intra- and peritumoural expression of FoxP3+-, CD8+-TIL and CD68+-, CD163+-TAM, contemplating cell density, cell ratios and cell-to-cell distances to determine a possible influence on tumour regression grade (TRG) and survival. Median follow-up time for all patients was 18 months (IQR 9–43), and 54 months (25–97) for surviving patients. Data were analysed using risk analysis, logrank test and Cox regression. Results Poor tumour regression was detected for cN+ (RR 0.77 [95% CI 0.66–0.90], p = 0.001), low intratumoural FoxP3+/CD8+ ratio (RR 0.75 [0.60–0.96], p = 0.020), high peritumoural CD163+/CD68+ ratio (RR 0.77 [0.60–0.99], p = 0.045) and high intratumoural TAM density (RD −0.44 [−0.82 to −0.06], p = 0.023). Apart from poor resection quality and TRG, pretherapeutic high peritumoural CD8+ infiltration (HR 2.36 [1.21–4.61], p = 0.012) and short intratumoural FoxP3+ to CD8+ cell-to-cell distances in middle ranged CD8+ density (HR 2.55 [1.00–6.52], p = 0.050) were significant unfavourable prognostic factors in multivariate analysis. Conclusions Immunologic parameters, such as CD8+-, FoxP3+-TIL and CD68+-, CD163+-TAM, were identified to be of independent predictive and prognostic value in patients with OAC. Further and independent validation of these biomarkers by a large size dataset may urgently be contemplated.

Background and purpose This multicenter, phase 3 trial investigates whether the incorporation of concurrent paclitaxel and cisplatin together with a reduced total dose of radiotherapy is superior to standard fluorouracil–cisplatin based CRT. Materials and methods Patients with SCCHN, stage III–IVB, were randomized to receive paclitaxel/cisplatin (PacCis)–CRT (arm A; paclitaxel 20 mg/m2 on days 2, 5, 8, 11 and 25, 30, 33, 36; cisplatin 20 mg/m2, days 1–4 and 29–32; RT to a total dose of 63.6 Gy) or fluorouracil/cisplatin (CisFU)–CRT (arm B; fluorouracil 600 mg/m2; cisplatin 20 mg/m2, days 1–5 and 29–33; RT: 70.6 Gy). Endpoint was 3-year-disease free survival (3y-DFS). Results A total of 221 patients were enrolled between 2010 and 2015. With a median follow-up of 3.7 years, 3y-DFS in the CisFU arm and PacCis arm was 58.2% and 48.4%, respectively (HR 0.82, 95% CI 0.56–1.21, p = 0.52). The 3y-OS amounted to 64.6% in the CisFU arm, and to 59.2% in the PacCis arm (HR 0.82, 95% CI 0.54–1.24, p = 0.43). In the subgroup of p16-positive oropharyngeal carcinomas, 3y-DFS and 3y-OS was 84.6% vs 83.9% (p = 0.653), and 92.3% vs. 83.5% (p = 0.76) in arm A and B, respectively. Grade 3–4 hematological toxicities were significantly reduced in arm A (anemia, p = 0.01; leukocytopenia, p = 0.003), whereas grade 3 infections were reduced in arm B (p = 0.01). Conclusion Paclitaxel/cisplatin–CRT with a reduced RT-dose is not superior to standard fluorouracil/cisplatin–CRT. Subgroup analyses indicate that a reduced radiation dose seems to be sufficient for p16+ oropharyngeal cancer or non-smokers. Clinical trial information: NCT01126216; EudraCT Number 2005-003484-23.

PURPOSE Total neoadjuvant therapy is a new paradigm for rectal cancer treatment. Optimal scheduling of preoperative chemoradiotherapy (CRT) and chemotherapy remains to be established. PATIENTS AND METHODS We conducted a multicenter, randomized, phase II trial using a pick-the-winner design on the basis of the hypothesis of an increased pathologic complete response (pCR) of 25% after total neoadjuvant therapy compared with standard 15% after preoperative CRT. Patients with stage II or III rectal cancer were assigned to group A for induction chemotherapy using three cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy) or to group B for consolidation chemotherapy after CRT. Secondary end points included toxicity, compliance, and surgical morbidity. RESULTS Of the 311 patients enrolled, 306 patients were evaluable (156 in group A and 150 in group B). CRT-related grade 3 or 4 toxicity was lower (37% v 27%) and compliance with CRT higher in group B (91%, 78%, and 76% v 97%, 87%, and 93% received full-dose radiotherapy, concomitant fluorouracil, and concomitant oxaliplatin in groups A and B, respectively); 92% versus 85% completed all induction/consolidation chemotherapy cycles, respectively. The longer interval between completion of CRT and surgery in group B (median 90 v 45 days in group A) did not increase surgical morbidity. A pCR in the intention-to-treat population was achieved in 17% in group A and in 25% in group B. Thus, only group B ( P < .001), but not group A ( P = .210), fulfilled the predefined statistical hypothesis. CONCLUSION Up-front CRT followed by chemotherapy resulted in better compliance with CRT but worse compliance with chemotherapy compared with group A. Long-term follow-up will assess whether improved pCR in group B translates to better oncologic outcome.

Importance Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established. Objective To report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer. Design, Setting, and Participants This secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population from June 15, 2015, to January 31, 2018, from 18 centers in Germany. Patients with cT3-4 and/or node-positive rectal adenocarcinoma were included in the analysis. Data were analyzed from June 15, 2015, to January 31, 2018. The follow-up analysis was conducted between January 31, 2018, and November 30, 2020. Interventions Patients were randomly assigned to group A for 3 cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy), or to group B for CRT before chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups. Main Outcomes and Measures The end points assessed in this secondary analysis included long-term oncologic outcomes, chronic toxicity, patient-reported outcome measures for global health status (GHS) and quality of life (QoL), and the Wexner stool incontinence score. Results Of the 311 patients enrolled, 306 were evaluable, including 156 in group A (mean [SD] age, 60 [11] years; 106 men [68%]) and 150 in group B (mean [SD] age, 62 [10] years; 100 men [67%]). After a median follow-up of 43 months (range, 35-60 months), the 3-year disease-free survival was 73% in both groups (hazard ratio, 0.95; 95% CI, 0.63-1.45,P = .82); the 3-year cumulative incidence of locoregional recurrence (6% vs 5%,P = .67) and distant metastases (18% vs 16%,P = .52) were not significantly different. Chronic toxicity grade 3 to 4 occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B at 3 years. The GHS/QoL score decreased after total mesorectal excision but returned to pretreatment levels 1 year after randomization with no difference between the groups. Stool incontinence deteriorated 1 year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels. Conclusions and Relevance This secondary analysis of a randomized clinical trial showed that CRT followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, QoL, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority. Trial Registration ClinicalTrials.gov identifier:NCT02363374

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.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.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 aged60 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.The addition of oxaliplatin significantly improved DFS and OS in younger patients aged60 years with advanced rectal cancer. Patients aged ≥70 years had no benefit.NCT00349076.

To retrospectively evaluate long-term treatment results following neoadjuvant chemoradiation (CRT) and radical surgery in patients with advanced adenocarcinoma (AC) of the oesophagus. Between 2005 and 2015, a total of 102 consecutive patients with a median age of 64 years (range, 44–86 years) and AC of the oesophagus were evaluated of whom 84 received a full CRT. A group of 51 patients was treated with neoadjuvant intent followed by radical surgery. A total dose of 50.4 Gy with mostly weekly paclitaxel/fluorouracil chemotherapy was administered. Six to eight weeks following CRT, a transthoracic subtotal oesophageal and proximal gastric resection was performed. Survival curves for overall survival and no evidence of disease (NED) survival (primary endpoints) were calculated according to Kaplan–Meier, and possible prognostic factors were evaluated by the log-rank test as well as by a Cox regression analysis. Median follow-up time of the surviving patients was 48 months (range, 14–134 months). Overall and NED survival rates for patients of the study group (n = 51) were 40 and 32%, respectively, at 5 years. Age (p = 0.04), ypT category (p = 0.1) and the development of distant metastases (p = 0.05) were identified as (marginally) independent prognostic variables with impact on survival. Median survival time for patients of the study group (n = 51) was 45 ± 18 months (95%CI 9–81 months). Clear resection margins were achieved in 46/51 patients (92%). Regression rates with complete regression rare residual cancer and increased number of residual cells, but predominantly fibrosis were 33, 41, and 10%, respectively. Patterns of failure revealed local with distant recurrence in 2/51 (4%), regional recurrence alone in 2/51 (4%), and distant metastases in 27/51 (53%) patients. Neoadjuvant CRT in patients with AC of the oesophagus followed by thoracoabdominal surgery is a locally very effective concept. A significant tumour regression in almost 75% of the patients may stimulate prospective trials on the omission of radical surgery for some elderly patients. Due to a high rate of distant metastases further investigations in terms of effective systemic therapy may be warranted.

Background: Concomitant radiation with BRAF inhibitor (BRAFi) therapy may increase radiation-induced side effects but also potentially improve tumour control in melanoma patients. Methods: A total of 155 patients with BRAF-mutated melanoma from 17 European skin cancer centres were retrospectively analysed. Out of these, 87 patients received concomitant radiotherapy and BRAFi (59 vemurafenib, 28 dabrafenib), while in 68 patients BRAFi therapy was interrupted during radiation (51 vemurafenib, 17 dabrafenib). Overall survival was calculated from the first radiation (OSRT) and from start of BRAFi therapy (OSBRAFi). Results: The median duration of BRAFi treatment interruption prior to radiotherapy was 4 days and lasted for 17 days. Median OSRT and OSBRAFi in the entire cohort were 9.8 and 12.6 months in the interrupted group and 7.3 and 11.5 months in the concomitant group (P=0.075/P=0.217), respectively. Interrupted vemurafenib treatment with a median OSRT and OSBRAFi of 10.1 and 13.1 months, respectively, was superior to concomitant vemurafenib treatment with a median OSRT and OSBRAFi of 6.6 and 10.9 months (P=0.004/P=0.067). Interrupted dabrafenib treatment with a median OSRT and OSBRAFi of 7.7 and 9.8 months, respectively, did not differ from concomitant dabrafenib treatment with a median OSRT and OSBRAFi of 9.9 and 11.6 months (P=0.132/P=0.404). Median local control of the irradiated area did not differ in the interrupted and concomitant BRAFi treatment groups (P=0.619). Skin toxicity of grade ≥2 (CTCAE) was significantly increased in patients with concomitant vemurafenib compared to the group with treatment interruption (P=0.002). Conclusions: Interruption of vemurafenib treatment during radiation was associated with better survival and less toxicity compared to concomitant treatment. Due to lower number of patients, the relevance of treatment interruption in dabrafenib treated patients should be further investigated. The results of this analysis indicate that treatment with the BRAFi vemurafenib should be interrupted during radiotherapy. Prospective studies are desperately needed.

Given the reduction in death from breast cancer, as well as improvements in overall survival, adjuvant radiotherapy is considered the standard treatment for breast cancer. However, left-sided breast irradiation was associated with an increased rate of fatal cardiovascular events due to incidental irradiation of the heart. Recently, considerable efforts have been made to minimize cardiac toxicity of left-sided breast irradiation by new treatment methods such as deep-inspiration breath-hold (DIBH) and new radiation techniques, particularly intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). The primary aim of this study was to evaluate the effect of DIBH irradiation on cardiac dose compared with free-breathing (FB) irradiation, while the secondary objective was to compare the advantages of IMRT versus VMAT plans in both the FB and the DIBH position for left-sided breast cancer. In all, 25 consecutive left-sided breast cancer patients underwent CT simulation in the FB and DIBH position. Five patients were excluded with no cardiac displacement following DIBH-CT simulation. The other 20 patients were irradiated in the DIBH position using respiratory gating. Four different treatment plans were generated for each patient, an IMRT and a VMAT plan in the DIBH and in the FB position, respectively. The following parameters were used for plan comparison: dose to the heart, left anterior descending coronary artery (mean dose, maximum dose, D25% and D45%), ipsilateral, contralateral lung (mean dose, D20%, D30%) and contralateral breast (mean dose). The percentage in dose reduction for organs at risk achieved by DIBH for both IMRT and VMAT plans was calculated and compared for each patient by each treatment plan. DIBH irradiation significantly reduced mean dose to the heart and left anterior descending coronary artery (LADCA) using both IMRT (heart –20%; p = 0.0002, LADCA –9%; p = 0.001) and VMAT (heart –23%; p = 0.00003, LADCA –16%; p = 0.01) techniques as compared with FB radiation. There were no significant changes in left lung dose by IMRT; however, with VMAT planning, mean dose to the left lung was reduced by –4% (p = 0.0004). In addition, DIBH significantly increased the mean dose to the contralateral breast with IMRT (+14%, p = 0.002) and significantly reduced the dose to the contralateral breast with VMAT planning (–9%, p = 0.003) compared with the FB position. Additionally, in comparison with VMAT, the IMRT technique reduced mean heart dose both in the FB and the DIBH-position by –30% (p = 0.0004) and –26% (p = 0.002), respectively. Furthermore, IMRT increased the mean dose to the left lung in both the FB and the DIBH position (+5%, p = 0.003, p = 0.006), respectively. There were no significant changes in dose to the right lung and contralateral breast either in the FB or DIBH position between IMRT and VMAT techniques. Left-sided breast irradiation is best performed in the DIBH position, since a considerable dose sparing to the heart and LADCA can be achieved by using either IMRT or VMAT techniques. A significant additional decrease in heart and LADCA dose by IMRT in both FB and DIBH irradiation was seen compared with VMAT.

Background Adjuvant radiotherapy is the standard treatment after breast-conserving surgery. According to meta-analyses, adjuvant 3d-conventional irradiation reduces the risk of local recurrence and thereby improves long-term survival by 5–10%. However, there is an unintended exposure of organs such as the heart, lungs and contralateral breast. Irradiation of the left breast has been related to long-term effects like increased rates of coronary events as well as second cancer induction. Modern radiotherapy techniques such as tangential intensity modulated radiotherapy (t-IMRT) and tangential volumetric modulated arc therapy (t-VMAT) and particularly deep inspiration breath hold (DIBH) technique have been developed in order to improve coverage of target volume and to reduce dose to normal tissue. The aim of this study was to compare t-IMRT-plans with t-VMAT-plans in DIBH position for left-sided breast irradiation in terms of normal tissue exposure, i.e. of lungs, heart, left anterior descending coronary artery (LADCA), as well as homogeneity (HI) and conformity index (CI) and excess absolute risk (EAR) for second cancer induction for organs at risk (OAR) after irradiation. Methods Twenty patients, diagnosed with left-sided breast cancer and treated with breast-preserving surgery, were included in this planning study. For each patient DIBH-t-IMRT plan using 5 to 7 beams and t-VMAT plan using four rotations were generated to achieve 95% dose coverage to 95% of the volume. Data were evaluated on the basis of dose-volume histograms: Cardiac dose and LADCA (mean and maximum dose, D25% and D45%), dose to ipsilateral and contralateral lung (mean, D20%, D30%), dose to contralateral breast (mean dose), total monitor units, V5% of total body and normal tissue integral dose (NTID). In addition, homogeneity index and conformity index, as well as the excess absolute risk (EAR) to estimate the risk of second malignancy were calculated. Results T-IMRT showed a significant reduction in mean cardiac dose of 26% (p = 0.002) compared to t-VMAT, as well as a significant reduction in the mean dose to LADCA of 20% (p = 0.03). Following t-IMRT, mean dose to the left lung was increased by 5% (p = 0.006), whereas no significant difference was found in the mean dose to the right lung and contralateral breast between the two procedures. Monitor units were 31% (p = 0.000004) lower for t-IMRT than for t-VMAT. T-IMRT technique significantly reduced normal tissue integral dose (NTID) by 19% (p = 0.000005) and the V5% of total body by 24% (p = 0.0007). In contrast, t-VMAT improved CI and HI by 2% (p = 0.001) and 0.4% (p = 0.00001), respectively. EAR with t-IMRT was significantly lower, especially for contralateral lung and contralateral breast (2–5/10,000 person years) but not for ipsilateral lung. Conclusion Compared to t-VMAT, t-IMRT in left-sided breast irradiation significantly reduced dose to organs at risk as well as normal tissue integral dose, and V5% total body. EAR with t-IMRT was significantly lower for contralateral lung and contralateral breast. T-VMAT, however, achieved better homogeneity and conformity. This may be relevant in individual cases where sufficient coverage of medial lymphatic target volumes is warranted.

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 individual-level 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

In their seminal work on adenocarcinoma of the esophago-gastric junction, Mitchell et al. (1) rise the important question of mediastinal nodal involvement specifically in patients with Siewert II/III cancer following trimodality therapy. The standard surgical adenocarcinoma of the esophago-gastric junction. As for treatment strategies include esophagectomy for type I and gastrectomy for type III “true junctional cancers”, i.e., type II, it remains debatable whether the extension of resection in the oral or aboral direction represents the most effective surgical therapy (2).

Summary Background Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy. Methods In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3–4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m 2 on days 1–5 and 29–33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m 2 on days 1–5 and 29); or to an investigational group receiving preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m 2 on days 1–14 and 22–35) and oxaliplatin (50 mg/m 2 on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m 2 on days 1 and 15), leucovorin (400 mg/m 2 on days 1 and 15), and infusional fluorouracil (2400 mg/m 2 on days 1–2 and 15–16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1–3 vs cT4), and clinical N category (cN0 vs cN1–2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076. Findings Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38–61), disease-free survival at 3 years was 75·9% (95% CI 72·4–79·5) in the investigational group and 71·2% (95% CI 67·6–74·9) in the control group (hazard ratio [HR] 0·79, 95% CI 0·64–0·98; p=0·03). Preoperative grade 3–4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3–4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3–4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group. Interpretation Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3–4 or cN1–2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer. Funding German Cancer Aid (Deutsche Krebshilfe).

Background We investigated tumor regression grading (TRG) as a prognostic marker and individual-level surrogate for disease-free survival (DFS) in patients with rectal carcinoma treated within the Chirurgische Arbeitsgemeinschaft fur Onkologie/Arbeitsgemeinschaft Radiologische Onkologie/Arbeitsgemeinschaft Internistische Onkologie (CAO/ARO/AIO)-04 randomized trial. Methods TRG was recorded prospectively using the Dworak classification in 1179 patients after preoperative fluorouracil-based chemoradiotherapy (CRT) with or without oxaliplatin. Multivariable analysis was performed using Cox regression models adjusted for treatment arm, resection status, and pathologic stage. Individual-level surrogacy of TRG for DFS was examined using the four Prentice criteria (PC1-4). All statistical tests were two-sided. Results With a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based CRT led to statistically significantly improved three-year DFS (75.9%, 95% CI = 72.3 to 79.5, vs 71.3%, 95% CI = 67.6 to 74.9, P = .04, PC 1) and a shift toward more advanced TRG groups ( P < .001, PC 2) compared with CRT with fluorouracil alone. The three-year DFS was 64.6% (95% CI = 57.3 to 71.9), 77.6% (95% CI = 74.5 to 80.7), and 92.3% (95% CI = 88.4 to 96.2) for TRG 0 + 1 (poor regression), TRG 2 + 3 (intermediate regression), and TRG 4 (complete regression), respectively ( P < .001, PC 3). TRG constituted an independent prognostic factor for DFS (TRG 2 + 3 vs TRG 0 + 1, HR = 0.68, 95% CI = 0.51 to 0.90, P = .007). Due to multicollinearity, TRG 4 and pathologic stage could not be tested within the same model. The treatment effect on DFS was captured by TRG, satisfying individual-level PC4. Conclusions Higher TRG after preoperative CRT predicted a favorable long-term outcome. At the individual patient level, TRG was a surrogate marker for DFS. Further phase III trials are needed to validate TRG as a surrogate at trial level.

Background In nonrandomized trials, neoadjuvant treatment was reported to prolong survival in patients with pancreatic cancer. As neoadjuvant chemoradiation is established for the treatment of rectal cancer we examined the value of neoadjuvant chemoradiotherapy in pancreatic cancer in a randomized phase II trial. Radiological staging defining resectability was basic information prior to randomization in contrast to adjuvant therapy trials resting on pathological staging. Patients and methods Patients with resectable adenocarcinoma of the pancreatic head were randomized to primary surgery (Arm A) or neoadjuvant chemoradiotherapy followed by surgery (Arm B), which was followed by adjuvant chemotherapy in both arms. A total of 254 patients were required to detect a 4.33-month improvement in median overall survival (mOS). Results The trial was stopped after 73 patients; 66 patients were eligible for analysis. Twenty nine of 33 allocated patients received chemoradiotherapy. Radiotherapy was completed in all patients. Chemotherapy was changed in 3 patients due to toxicity. Tumor resection was performed in 23 vs. 19 patients (A vs. B). The R0 resection rate was 48 % (A) and 52 % (B, P = 0.81) and (y)pN0 was 30 % (A) vs. 39 % (B, P = 0.44), respectively. Postoperative complications were comparable in both groups. mOS was 14.4 vs. 17.4 months (A vs. B; intention-to-treat analysis; P = 0.96). After tumor resection, mOS was 18.9 vs. 25.0 months (A vs. B; P = 0.79). Conclusion This worldwide first randomized trial for neoadjuvant chemoradiotherapy in pancreatic cancer showed that neoadjuvant chemoradiation is safe with respect to toxicity, perioperative morbidity, and mortality. Nevertheless, the trial was terminated early due to slow recruiting and the results were not significant. ISRCTN78805636; NCT00335543. Electronic supplementary material The online version of this article (doi: 10.1007/s00066-014-0737-7) contains supplementary material, which is available to authorized users.

In various cancer types, an abundance of FoxP3(+) regulatory T cells (Treg) has been associated with an unfavorable outcome. Yet, the role of Treg on cancer immunity has been shown to be complex. In single cell marker technique, other tumor-infiltrating lymphocytes (TILs) such as cytotoxic CD8(+) T cells (CTL) also influenced prognosis. This study for the first time investigates the concurrent spatial distribution pattern of CD8(+) and FoxP3(+) TILs and their prognostic impact in human gastric cancer.Tumor tissue microarrays of 50 patients with surgically treated adenocarcinoma of the cardia were studied. An immunohistochemical double staining of CD8(+) and FoxP3(+) TILs was performed. Cell counts and cell-to-cell distances in tumor epithelium and stroma were evaluated with image-processing software. Metastasis-free survival, no-evidence-of-disease survival, and overall survival were investigated (mean follow-up time 6.9 years).High intraepithelial infiltration of CD8(+) and FoxP3(+) TIL was associated with the improved 10-year metastasis-free survival (83 vs. 54%, p = 0.04 and 85 vs. 59%, p = 0.09, respectively). Considering cell-to-cell distance and comparing patients with functional (30-110 μm) versus nonfunctional distances of CD8(+) and FoxP3(+) TILs, 10-year survival rates differed between 89 and 55% (p = 0.009), respectively.Prognostic influence of tumor-infiltrating immune cells in gastric cancer critically depends on their cell-to-cell distance. FoxP3(+) TILs must be located within a distance between 30 and 110 μm of CD8(+) T cells to positively impact on prognosis.

BACKGROUND AND PURPOSE: Neoadjuvant chemoradiation could improve survival in patients with pancreatic cancer because of a higher rate of R0 resections, lower rate of nodal metastasis (ypN) and of local recurrence. This approach was tested in a cohort to estimate its effect on survival. PATIENTS AND METHODS: Three-dimensional, conformal radiation to the primary tumor (55.8 Gy) and the lymphatics (50.4 Gy) was combined with chemotherapy. Resection was performed 6 weeks after completion of chemoradiation. RESULTS: 38 of 120 patients with locally advanced cancer underwent tumor resection thereafter. Three patients (8%) had pathologic complete response. Median tumor-specific survival was 29 months and overall survival 25 months. Patients with clear margins (35/38; 89%) had a 3-year disease-specific survival rate of 51% versus 0% with positive margins (p = 0.008). Nodal disease rate decreased from 50% at pretherapeutic imaging to 32% at resection. Patients with ypN0 status (n = 26/38) had a 3-year tumor-specific survival rate of 50% compared to 31% in patients with ypN1 status. At multivariate analysis, resection status and nodal spread significantly predicted tumor-specific survival. Chemoradiation was generally well tolerated. CONCLUSION: The current results support randomized testing of neoadjuvant chemoradiation to prove survival prolongation. Compared to the literature this approach seems to reduce the number of positive nodes.

Possible toxic effects following radiation and chemotherapy of gastrointestinal tumours may cause a depletion of the mucosal barrier within the radiation volumes with severe mucositis. Diarrhoea, nausea, emesis and severe malabsorption followed by infections with dehydration and electrolyte disorders have to be encountered. For prevention and treatment of oropharyngeal mucositis an oral care protocol, oral cryotherapy together with benzydamine mouthwash may be recommended. Lower gastrointestinal diarrhoea is best treated by Octreotide (>100 μg s.c. bid) if loperamide is ineffective and amifostine (340 mg/m 2 IV) to prevent radiation proctitis. Enteral nutrition may be necessary with severe malnutrition or no enteral food intake for >7days or insufficient intake ( 10 days. With severe generalized mucositis or severe radiation induced enteritis parenteral nutrition will be initiated. Following the application of highly emetogenic chemotherapy regimen, 5-HT3 antagonists, dexamethasone and aprepitant, whereas in moderate risk levels 5-HT3 antagonist plus dexamethasone may be sufficient.

BACKGROUND Until the mid of this century, 33% of the Western population will be > or = 65 years old. The percentage of patients being > or = 80 years old with today 5% will triple until 2050. Therefore, radiation oncologists must be familiar with special geriatric issues to meet the increasing demand for multidisciplinary cooperation and to offer useful and individual treatment concepts. PATIENTS AND METHODS This review article will provide basic data on the definition, identification and treatment of geriatric cancer patients. RESULTS The geriatric patient is defined by typical multimorbidity (15 items) and by age-related increased vulnerability. Best initial identification of geriatric patients will be provided by assessment including the Barthel Index evaluating self-care and activity in daily life, by the Mini-Mental Status Test that will address cognitive pattern, and by the Timed "Up&Go" Test for evaluation of mobility. As for chemotherapy, standard treatment was associated with increased toxicity, consequently, dose modifications and supportive treatment are of special importance. CONCLUSION Geriatric cancer patients need to be identified by special assessment instruments. Due to increased toxicity following chemotherapy, supportive measures seem important. Radiation treatment as a noninvasive and outpatient-based treatment remains an important and preferable option.

The present experimental study sought to determine the effect of high-dose irradiation on the rat mandible in order to establish an experimental model of radiogenic bone damage. The left mandibles of 20 adult Wistar rats were irradiated (single fraction 1500cGy, total dose 60Gy) by means of a hypofractionated stereotactic radiotherapy (hfSRT) over a period of 6 weeks. Follow-up was 6 weeks (group 1, n=10) and 12 weeks (group 2, n=10). The contralateral mandibles as well as 5 non-irradiated animals served as controls. Primary endpoints were fibrosis, loss of cell count, decreased immunohistochemical labelling for bone morphogenetic protein-2 (BMP-2) and osteocalcin as well as increased expression of transforming growth factor (TGF-beta). Cell loss, progressive fibrosis, and focal necrosis were detected in all irradiated sites. Quantitative measurement revealed 32.0+/-8.7% and 37.3+/-9.5% empty osteocyte lacunae for groups 1 and 2 resp., compared to 16.3+/-4.7% and 18.9+/-4.9% on the contralateral side and 7.9+/-1.7% for unirradiated controls (Mann-Whitney U test; p

Introduction: Irradiation of brain tumors (BT) in children can lead to the loss of pituitary function, predominantly manifesting as deficiencies in GH and ACTH. Objective: To assess the incidence and nature of pituitary deficiency in relation to initial tumor location in children after radiotherapy of BT. Methods: Twenty survivors (16 males and 4 females) of radiation-treated BT aged 1.4–10.9 (median 3.6) yr at diagnosis were studied, 10 with supratentorial and 10 with infratentorial BT. Radiation doses to the hypothalamus-pituitary (HP) area ranged from 30 to 54 (median 45) Gray. Follow-up was 9.4–16.9 (median 12.2) yr. Basal pituitary hormone levels were measured every 6 months. When growth failure became evident or pituitary deficiency was suspected, provocation tests of the HP axis were performed to assess GH, ACTH, and TSH function. Results: GH deficiency (GHD) developed in 17/20 (85%) children. In 10 patients, it occurred 4 yr after radiotherapy and in 2, 11 and 12 yr after radiotherapy. Six (30%) patients developed secondary hypothyroidism and 4 (20%) developed ACTH deficiency. Precocious puberty occurred in 2 girls. The course of development and the severity of hormone deficiencies were similar for supratentorial and infratentorial tumors. Conclusion: The major hormonal effect of BT irradiation in children is GHD, which may sometimes take more than 10 yr to manifest. We confirm findings by others that ACTH insufficiency occurs less frequently in children than reported for adults. Tumor location has no prognostic significance regarding the loss of HP function.

Classical Hodgkin Lymphoma (cHL) is morphologically characterized by a small number of tumour cells, Hodgkin and Reed-Sternberg (HRS) cells, surrounded by numerous tumour-infiltrating lymphocytes (TIL). The functional role of these TIL is still controversial. While generally considered to represent an anti-tumour immune response, TIL in cHL might result from the profoundly deregulated immunity of cHL patients. Eighty-seven cases of cHL were available to evaluate the prognostical significance of tumour-infiltrating cytotoxic T lymphocytes (CTL), T helper 1 (Th1) cells, T helper 2 (Th2) cells and regulatory T cells (Treg). We confirm that in cHL the microenvironment is dominated by Th2 cells and Treg and show that large numbers of Th2 cells are associated with significantly improved disease-free survival (p = 0.021) and event-free survival (p = 0.012). Furthermore, a high ratio of Treg over Th2 cells resulted in a significantly shortened disease-free survival (p = 0.025). These observations suggest that Treg may exert inhibitory effects on anti-tumour immune responses mediated through Th2 cells and that Th2 cells may be more important for effective anti-tumour immunity than anticipated.

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 x 2 Gy) alone with WBRT+topotecan (RCT; 0.4 mg m(-2) day(-1) x 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.

Aims To evaluate a single centre's experience with pancreatic carcinoma focused on preoperative chemoradiation therapy (CRT) for treatment of locally advanced pancreatic carcinoma. The aim of the present analysis was to evaluate the median overall survival time (OS) after preoperative CRT and to compare it with OS after primary resection of pancreatic carcinoma. In conclusion a new treatment strategy was developed using multimodality treatment for pancreatic carcinoma deemed to be resectable by CT-scan. Patients and methods Between 1995 and 2003, 302 patients with ductal adenocarcinoma of the pancreatic head and body were recorded prospectively and OS was analysed with regard to therapy. Results Fifty-eight patients were resected without any pretreatment and had an OS of 21 months. Twenty-one patients with initially unresectable tumours underwent CRT followed by resection and had an OS of 54 months, which was not significantly different from primary resection ( p =0.315). Lymph node metastasis was significantly reduced after CRT ( p =0.0029). OS for patients whose tumours could not be resected was 3–10 months, depending on tumour stage and consecutive therapy. Conclusion CRT pretreatment was effective in locally advanced pancreatic carcinoma and resulted in resection of tumours otherwise staged as non-resectable. This experience led to a randomized trial for patients who by CT are staged to have resectable cancer of the pancreatic head with the intent to increase curative resectability and survival by neoadjuvant CRT (ISRCTN78805636/NCT00335543).

Purpose Preclinically, HIV protease inhibitors radiosensitize tumors with activated PI3-kinase/Akt pathway. We determined the toxicity of nelfinavir chemoradiotherapy in borderline resectable and unresectable pancreatic cancer. Patients and Methods Oral nelfinavir (2 × 1,250 mg) was started 3 days before and continued throughout chemoradiotherapy to 50.4 Gy (boost, 59.4 Gy) in 12 patients. Two gemcitabine dose levels (DL) were tested (200 mg/m2 and 300 mg/m2 on days 1, 8, 22, and 29). Cisplatin was administered on the same days at 30 mg/m2. Phospho-Akt downregulation by nelfinavir was monitored by immunoblotting in patient leukocytes. Restaging positron emission tomography (PET)/computed tomography (CT) and CA19-9 levels served to assess response, and responding tumors were resected. Results At each DL, five of six patients completed chemoradiotherapy, and two of 12 patients had incomplete chemoradiotherapy because of clinical depression (DL1) and peritoneal metastasis (DL2). Grade 4 toxicities were a transaminase elevation (DL2) as a result of biliary stent occlusion and acute cholecystitis as a result of peritoneal metastasis (DL2). Stent occlusions led to dose-limiting toxicities of grade 3 liver enzyme and bilirubin elevations (two patients at DL1, one patient at DL2). Grade 3 nausea and vomiting occurred in a DL2 patient, and weight loss occurred in a DL1 patient who refused supportive feeding. Secondary complete resection was possible in six of 10 patients with complete chemoradiotherapy, including one tumor with pathologic sterilization. Partial CT responses were observed in five of 10 patients who completed chemoradiotherapy. Of nine patients assessable by PET,responses were complete in five patients and partial patients, and stable disease was observed in two patients. Conclusion The combination of nelfinavir and chemoradiotherapy showed acceptable toxicity and promising activity in patients with pancreatic cancer.

Anhand der Ergebnisse der multidisziplinaren Behandlung lokalisierter Ewing-Sarkome sollten prognostisch relevante Faktoren herausgearbeitet werden, die Einfluss auf das Langzeituberleben und das lokalrezidivfreie Uberleben nehmen. Zwischen 1979 und 2004 wurden 60 Kinder und Jugendliche mit einem Ewing-Sarkom behandelt. Ausgeschlossen wurden Patienten mit primaren Fernmetastasen (n = 6) und im Rezidivfall vorgestellte (n = 2) Patienten. Die Patienten wurden ausnahmslos im Rahmen der jeweils aktuellen Protokolle CESS-81, CESS-86, EICESS-92, EURO-EWING-99 multimodal behandelt. Alle Patienten wurden lokal mit 45–60 Gy bestrahlt, 41 Patienten (79%) einer Primartumorresektion unterzogen, davon wurden 27 (52%) R0-operiert. Die 5- und 10-Jahres-Uberlebensraten lagen bei 56% und 45%. Die Gruppe der jungeren Patienten (≤ 14 Jahre) hatte eine 5- und 10-Jahres-Uberlebensrate von 66% und 61%, bei den alteren betrug diese nach 5 Jahren 47% und nach 10 Jahren 31% (p = 0,05). Patienten mit einer geringeren Tumorlast (≤ 100 ml Tumorvolumen) wiesen mit 82% und 60% signifikant gunstigere 5- und 10-Jahres-Uberlebensraten auf als Patienten mit einer groseren Tumorlast (42% und 39%; p = 0,03). Sieben der 52 Patienten (14%) erlitten ein lokales Rezidiv, wobei weder das Behandlungsprotokoll, die Dosis der Radiotherapie noch die Radikalitat der Resektion einen signifikanten Einfluss zeigten. Die Radiotherapie des Ewing-Sarkoms stellt sowohl allein als auch in Kombination mit der Resektion eine hocheffektive Lokaltherapie dar. Sie muss in jedem Fall einer mutilierenden Operation vorgezogen werden.

Purpose To present the results of a prospective phase II study in esophageal carcinoma. Patients and methods Patients received single doses of 1.8 Gy up to 27 Gy, then concomitant boost to a total of 50.4 Gy (PTV2 [planning target volume], single dose 1.8 Gy) and 64.8 Gy (PTV1, single dose 1.2 Gy in the morning and 1.8 Gy in the afternoon) concurrently with 800 mg/m(2)/d 5-fluorouracil and 20 mg/m(2)/d cisplatin (weeks 1 and 5). High-dose-rate brachytherapy (2-3 x 6 Gy) on Fridays of weeks 4-6 used a customized applicator facilitating central placement and circumferential dose homogeneity. Results 50 patients with squamous cell carcinoma (90%) or adenocarcinoma and mostly advanced tumor stage were treated (82% T3/T4 and 70% N1). Median overall survival (median OS 16 months; 1-year-OS 61%; 2-year OS 29%) was significantly longer for patients without nodal disease (35 vs. 11 months; p = 0.01). Hematotoxicity was grade 3 in 11/50, and grade 4 in 1/50 patients. Four percent of higher-grade nausea or vomiting occurred. Esophageal late toxicity was grade 3 in 9/50 patients, and grade 4 in 2/50 patients. Conclusion Survival was excellent especially for patients without nodal disease in this dose-intensified schedule with acceptable tolerability.

Introduction Recently new concepts for the treatment of oral squamous cell carcinomas (SCC) have been developed, which include preoperative simultaneous neoadjuvant radiochemotherapy (RCT) and one stage operation with excision of the tumour and reconstruction. When we consider long-term survival, we find substantial evidence that combined treatment based on neoadjuvant radiochemotherapy is superior to adjuvant treatment including operation and postoperative radiation. Patients and methods We studied two groups consisting of 74 patients given neoadjuvant treatment and 54 treated surgically. Ninety-nine patients suffered from stage III and IV diseases according to the UICC-criteria. Long-term survival was estimated by the Kaplan–Meier method. Results Neoadjuvant treatment increased the prospect of a long-term survival free of tumour. Kaplan–Meier curves estimated a 5-year tumour-free survival in oral squamous cell carcinoma category T1 as 83% in the neoadjuvant group and 70% in the adjuvant group; the corresponding figures for T2 were 79% and 57%, for T3 68% and 33% and for T4 51% and 30%, respectively. The difference for T1, T2 and T4 tumours were significant. The preoperative radio- and chemotherapy were shown to be effective by the fact that pathohistologically resection specimens were free of tumour in 28 patients in the neoadjuvant group. Four patients died during the preoperative combination treatment. Of the patients, 65% in the adjuvant group and 72% in the neoadjuvant group survived the observation period. Conclusion The neoadjuvant treatment results in better 5-year-survival rate than adjuvant treatment.

To evaluate efficacy and toxicity of hypofractionated stereotactic radiotherapy (hfSRT) with three different dose concepts for irresectable brain metastases not amenable to radiosurgery (SRS) using non-invasive fixation of the skull. From 6/2000 to 6/2005, 150 patients with 228 brain metastases were treated at the dedicated stereotactic radiosurgery system Novalis™ (BrainLAB, Feldkirchen, Germany) in two German treatment centers. Three different dose concepts were applied: 5 x 6–7 Gy (A: 72 brain metastases), 10 x 4 Gy (B: 59 brain metastases) and 7 x 5 Gy (C: 97 brain metastases). Median planning target volume (PTV) was 6.1 cm3 (range, 0.02–95.97). Rates of complete remission (CR), partial remission (PR), no change (NC) and progressive disease (PD) were 42%, 30%, 21% and 7%, respectively (median follow-up 28 months). Median survival was 16 months. Survival at 6 and 12 months was 83% and 66%, respectively. Side effects were dependent on the PTV and on dose concept (median PTV in case of increasing edema or necrosis: 17 cm3, A: 22%, C: 7%). HfSRT with 10 x 4 Gy (B) was well tolerated without side effects. Hypofractionated stereotactic radiotherapy is an effective and safe treatment. In case of brain metastases > 15 cm3 (diameter > 3 cm) and concerning toxicity, 10 x 4 Gy seem to be more advantageous than shorter fractionation with higher doses while 5 x 6–7 Gy and 7 x 5 Gy were followed by higher response rates. Further specification of tolerance doses and tolerance according to the different brain regions has to be done.

To determine the effect of hypofractionated stereotactic radiotherapy (hfSRT) on adult rat brain tissue (necrosis, impact on blood-brain barrier, signal changes on high-field magnetic resonance imaging [MRI]). Adult male Wistar rats underwent MRI and CT scanning of the brain and respective images were introduced into the Novalis™ radiosurgery device (BrainLab, Feldkirchen, Germany). All animals (body weight 350 g) were irradiated weekly with doses of 2 × 10 Gy (n = 3 animals), 3 × 10 Gy (n = 3 animals) and 4 × 10 Gy (n = 3 animals), targeted to the left hippocampus after image-guided positioning. 4.7-T T2-weighted MRI scanning was performed in each animal. Animals were sacrificed 8, 12, and 16 weeks after hfSRT and brains were immersion-fixed in 4% paraformaldehyde for subsequent histopathologic analysis. In concordance with isodose distributions, pathologic signal hyperintensities in MRI were recorded from 4 × 10 Gy after 8 weeks, 3 × 10 Gy after 12 weeks, while 2 × 10 Gy induced slight detectable alterations only after 16 weeks. Subsequent histopathologic analysis revealed hippocampal cell necrosis with significantly earlier and stronger occurrence for higher doses (40 Gy > 30 Gy > 20 Gy). Pial microvessel permeability also increased after 40 Gy, whereas 30 Gy induced moderate changes. Conclusion: Partial-brain irradiation with hfSRT (Novalis™ System) was successfully adopted for small animals and histopathologic analysis confirmed its repositioning accuracy. The neuropathologic effects correlated with dose and observation time. The approach will be further developed for quality assurance in hfSRT of normal brain tissue, as well as novel treatment modalities in epileptic rats and orthotopic tumor models.

DNA double-strand breaks (dsbs) in lymphoblastoid cell lines (LCLs), fibroblasts and white blood cells from healthy donors, cancer patients with and without late effects of grade 3–4 (RTOG) as well as donors with known radiosensitivity syndromes were examined with the aim to detect dsb repair ability as a marker for radiosensitivity. LCLs from six healthy donors, seven patients with a heterozygous or homozygous genotype for ataxiatelangiectasia (ATM) and Nijmegen breakage syndrome (NBS), two patients with a late toxicity of grade 3–4 (RTOG), and one cell line with a ligase IV–/– status and its parental cell line were examined. Furthermore, fibroblasts from patients with ATM, NBS, two healthy control individuals, and leukocytes from 16 healthy and 22 cancer patients including seven patients with clinical hypersensitivity grade 3 (RTOG) were examined. Cells were irradiated in vitro with 0–150 Gy. Initial damage as well as remaining damage after 8 and 24 h were measured using constant field gel electrophoresis. In contrast to cells derived from patients homozygous for NBS, impaired dsb repair ability could be detected both in fibroblast and lymphoblastoid cells from ATM and ligase IV–/– patients. The dsb repair ability of all 38 leukocyte cell lines (patients with grade 3–4 late effects and controls) was similar, whereas the initial damage among healthy donors was less. Despite showing a clinically elevated radiosensitivity after irradiation, the DNA repair of the patients with clinical hypersensitivity grade 3 (RTOG) appeared to be normal. Other mechanisms such as mutations, altered cell cycle or defective apoptosis could play a critical role toward determining radiosensitivity.

Das Plattenepithelkarzinom der Mundhohle gehort zu den zehn haufigsten malignen Tumoren. Die Prognose des Mundhohlenkarzinoms in fortgeschrittenen Stadien ist nach wie vor schlecht. In dieser Studie werden die Ergebnisse zweier Behandlungskonzepte zur neoadjuvanten und adjuvanten Kombinationstherapie vorgestellt. In einer nichtrandomisierten prospektiven Studie wurden insgesamt 128 Patienten mit Plattenepithelkarzinomen der Mundhohle beurteilt. Eine Gruppe (74 Patienten) wurde neoadjuvant mit einer kombinierten Radiochemotherapie vorbehandelt und anschliesend einer Tumorresektion unterzogen. Die verbliebenen 54 Patienten wurden primar chirurgisch behandelt und postoperativ bestrahlt. Insgesamt 99 Patienten befanden sich in den UICC-Stadien III und IV. Die 5-Jahres-Uberlebenswahrscheinlichkeit wurde nach Kaplan-Meier statistisch ermittelt. Nach 5-jahriger Beobachtungszeit kann fur neoadjuvant vorbehandelte Patienten ein Uberlebensvorteil gegenuber adjuvant behandelten Patienten festgestellt werden. Nach Kaplan-Meier betragt die Uberlebenswahrscheinlichkeit fur Tumoren der Kategorie T1 83,1% neoadjuvant gegenuber 70,1% adjuvant, fur T2 79,6% bzw. 57,7%, fur T3 68,2% bzw. 33,2% und fur T4 51,4% bzw. 30,5%. Signifikant bessere Ergebnisse (p < 0,05) konnten fur Tumoren im Stadium T1 (p = 0,002), T2 (p = 0,028) und T4 (p < 0,0001) ermittelt werden. Die praoperative Kombinationsbehandlung fuhrte bei 28 Patienten zur Elimination des Tumors (37,8%). 64,8% der adjuvant und 71,6% der neoadjuvant behandelten Patienten lebten am Ende des Beobachtungszeitraums. Neoadjuvant behandelte Patienten konnen mit einer signifikant hoheren Wahrscheinlichkeit langfristig tumorfrei uberleben. Jeder Patient mit einem primaren Plattenepithelkarzinom der Mundhohle sollte einer Kombinationstherapie zugefuhrt werden. Die dadurch mogliche Reduktion des chirurgischen Eingriffs wird den Funktionserhalt und damit auch die Lebensqualitat der betroffenen Patienten verbessern.