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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.

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.

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).

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.

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.

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.

BACKGROUND AND PURPOSE: Despite the enormous therapeutic potential of modern radiotherapy, common side effects such as radiation-induced wound healing disorders remain a well-known clinical phenomenon. Topical negative pressure therapy (TNP) is a novel tool to alleviate intraoperative, percutaneous irradiation or brachytherapy. Since TNP has been shown to positively influence the perfusion of chronic, poorly vascularized wounds, the authors applied this therapeutic method to irradiated wounds and investigated the effect on tissue oxygenation in irradiated tissue in five patients. MATERIAL AND METHODS: With informed patients' consent, samples prior to and 4 and 8 days after continuous TNP with -125 mmHg were obtained during routine wound debridements. Granulation tissue was stained with hematoxylin-eosin, and additionally with CD31, HIF-1 alpha (hypoxia-inducible factor-1 alpha), and D2-40 to detect blood vessels, measure indirect signs of hypoxia, and lymph vessel distribution within the pre- and post-TNP samples. RESULTS: In this first series of experiments, a positive influence of TNP onto tissue oxygenation in radiation-induced wounds could be demonstrated. TNP led to a significant decrease of 53% HIF-1 alpha-positive cell nuclei. At the same time, a slight reduction of CD31-stained capillaries was seen in comparison to samples before TNP. Immunostaining with D2-40 revealed an increased number of lymphatic vessels with distended lumina and an alteration of the parallel orientation within the post-TNP samples. CONCLUSION: This study is, to the authors' knowledge, the first report on a novel previously not described histological marker to demonstrate the effects of TNP on HIF-1 alpha expression as an indirect marker of tissue oxygenation in irradiated wounds, as demonstrated by a reduction of HIF-1 alpha concentration after TNP. Since this observation may be of significant value to develop possible new strategies to treat radiation-induced tissue injury, further investigations of HIF-1 alpha regulation under TNP are warranted.

Background: Recent evidence suggests that ionizing radiation may be associated with unexpected side-effects in melanoma patients treated with concomitant BRAF inhibitors. A large multicenter analysis was carried out to generate reliable safety data and elucidate the mechanism. Methods: A total of 161 melanoma patients from 11 European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence in situ hybridization of chromosomal breaks after ex vivo irradiation. Results: With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis ≥2° was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole-brain radiotherapy, rates of radiodermatitis ≥2° were 44% and 8% (P < 0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis ≥2° more frequently than treatment with dabrafenib (40% versus 26%, P = 0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (P = 0.004) and for patients switched from vemurafenib to dabrafenib (P = 0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment. Conclusion: Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib.

Purpose To report the long-term results of the ARO 95-06 randomized trial comparing hyperfractionated accelerated chemoradiation with mitomycin C/5-fluorouracil (C-HART) with hyperfractionated accelerated radiation therapy (HART) alone in locally advanced head and neck cancer. Patients and Methods The primary endpoint was locoregional control (LRC). Three hundred eighty-four patients with stage III (6%) and IV (94%) oropharyngeal (59.4%), hypopharyngeal (32.3%), and oral cavity (8.3%) cancer were randomly assigned to 30 Gy/2 Gy daily followed by twice-daily 1.4 Gy to a total of 70.6 Gy concurrently with mitomycin C/5-FU (C-HART) or 16 Gy/2 Gy daily followed by twice-daily 1.4 Gy to a total dose of 77.6 Gy alone (HART). Statistical analyses were done with the log-rank test and univariate and multivariate Cox regression analyses. Results The median follow-up time was 8.7 years (95% confidence interval [CI]: 7.8-9.7 years). At 10 years, the LRC rates were 38.0% (C-HART) versus 26.0% (HART, P =.002). The cancer-specific survival and overall survival rates were 39% and 10% (C-HART) versus 30.0% and 9% (HART, P =.042 and P =.049), respectively. According to multivariate Cox regression analysis, the combined treatment was associated with improved LRC (hazard ratio [HR]: 0.6 [95% CI: 0.5-0.8; P =.002]). The association between combined treatment arm and increased LRC appeared to be limited to oropharyngeal cancer ( P =.003) as compared with hypopharyngeal or oral cavity cancer ( P =.264). Conclusions C-HART remains superior to HART in terms of LRC. However, this effect may be limited to oropharyngeal cancer patients.

To evaluate the feasibility, efficacy, and side effects of dose escalation in hypofractionated stereotactic radiotherapy (hfSRT) for intrapulmonary tumors with the Novalis™ system (BrainLAB AG, Heimstetten, Germany). From 07/2003 to 01/2005, 21 patients/39 tumors were treated with 5 × 7 Gy (n = 21; total dose 35 Gy) or 5 × 8 Gy (n = 18; total dose 40 Gy). There were three cases of primary lung cancer, the remainder were metastases. Median gross tumor volume (GTV) and planning target volume (PTV) were 2.89 cm3 (range, 0.15–67.94 cm3) and 25.75 cm3 (range, 7.18–124.04 cm3), respectively. Rates of complete remission, partial remission, no change, and progressive disease were 51%, 33%, 3%, and 13%, respectively. No grade 4 toxicity occurred, nearly all patients had grade 1 initially. One grade 3 toxicity, i.e., dyspnea, was documented for a period of 6 months after therapy. Radiosurgery quality assurance guidelines could be met. hfSRT of primary and secondary lung tumors using a schedule of five fractions at 7–8 Gy each was well tolerated. Further dose escalation is planned.

Background Radiosensitivity of normal tissue is a crucial factor of radiotherapy (RT)-related side effects. Here, we report the analysis of spontaneous and in vitro irradiation-induced chromosomal aberrations in 256,679 metaphases from 222 different individuals using three-color fluorescence in situ hybridization as a measure of radiosensitivity. Materials and methods Samples were categorized into the following 6 groups: (1) healthy individuals, (2) cancer patients prior to radiotherapy, (3) RT-treated cancer patients, (4) individuals heterozygous or (5) homozygous for a mutation in the ataxia telangiectasia mutated (ATM) gene or in the Nijmegen breakage syndrome (NBS1) gene and (6) hypersensitive patients (outliers). Results A normal distribution of the number of chromosomal aberrations, measured as breaks per metaphase (B/m), was adopted for all examined groups. The mean value of the control group was 0.40 B/m (SD ± 0.07). This value was lower compared to the mean breakage rate from 175 non-exposed (0.50 ± 0.12 B/m) and pre-exposed (0.50 ± 0.16 B/m) cancer patients. Nineteen of the metaphase spreads from the analyzed cancer patients had a high number of chromosomal aberrations (1.04 ± 0.29 B/m) and were designated as a separate hypersensitive subgroup (outliers). The aberration frequency of this group was comparable to those of ATM or NBS1 heterozygotes (0.86 ± 0.26 B/m). The highest incidence of aberrations was observed in ATM and NBS1 homozygous patients (2.23 ± 1.03 B/m). Conclusion The frequency of break events in the analyzed groups resulted in a normal distribution with varying means and broadnesses defining a characteristic sensitivity pattern for each group. In the RT-relevant group of cancer patients, those patients who have cancer, about one-third of the normally distributed samples were determined to be sensitive as defined by the number of induced aberrations higher than the 99% confidence interval of the normal individual’s Gaussian distribution. About 5% of these samples were outside of the 99% confidence interval for the RT-relevant group’s normal distribution. These outliers with higher chromosomal breakage rates suggest a unique class of hypersensitive individuals that are susceptible to chromosomal damage and may be directly associated with an increased risk to suffer from radiotherapy-related complications.

Currently, there is no treatment standard for patients with locally advanced pancreatic cancer (PaCa) after chemoradiation. The aim of the present study was to retrospectively assess overall survival and toxicity of chemotherapy in addition to chemoradiation in this patient group. Three-dimensional conformal irradiation to the primary tumor (55.8 Gy) and the lymphatics (50.4 Gy) was combined with 5-fluorouracil- or gemcitabine-based chemotherapy followed by additional chemotherapy with gemcitabine until progression or no further treatment. Decision for chemotherapy was taken at the discretion of the attending physician considering the patient’s desire. A total of 172 patients were addressed to the local tumor board. Patients with (neo)adjuvant treatment or metastatic disease were excluded (n = 90). 82 patients were treated with chemoradiation and had additional chemotherapy (n = 40) or no further treatment (n = 42). Characteristics of the two groups were equally distributed. Patients with chemotherapy had significantly longer overall survival as compared to patients without (13 months vs. 8 months; p < 0.0001; median survival = 10.7 months for all patients). Acute toxicity of maintenance chemotherapy was relatively mild. Maintenance chemotherapy after chemoradiation for patients with locally advanced PaCa may significantly increase survival rates without severe side effects and is therefore recommended as standard treatment following chemoradiation.

Plasminogen activator inhibitor (PAI)-1 mediates transforming growth factor-beta1 (TGF-beta1)-related signaling by stimulating collagen Type I synthesis in radiation-impaired wound healing. The regulation of alpha(I)-procollagen is contradictory in fibroblasts of different fibrotic lesions. It is not known whether anti-TGF-beta1 treatment specifically inhibits alpha(I)-procollagen synthesis. We used an experimental wound healing study to address anti-TGF-beta1-associated influence on alpha(I)-procollagen synthesis.A free flap was transplanted into the preirradiated (40 Gy) or nonirradiated neck region of Wistar rats: Group 1 (n = 8) surgery alone; Group 2 (n = 14) irradiation and surgery; Group 3 (n = 8) irradiation and surgery and anti-TGF-beta1 treatment. On the 14th postoperative day, skin samples were processed for fibroblast culture, in situ hybridization for TGF-beta1, immunohistochemistry, and immunoblotting for PAI-1, alpha1/alpha2(I)-procollagen.Anti-TGF-beta1 significantly reduced TGF-beta1 mRNA (p0.05) and PAI-1 expression (p0.05). Anti-TGF-beta1 treatment in vivo significantly reduced alpha1(I)-procollagen protein (p0.05) and the number of expressing cells (p0.05) in contrast to significantly increased (p0.05) alpha2(I)-procollagen expression.These results emphasize anti-TGF-beta1 treatment to reduce radiation-induced fibrosis by decreasing alpha1(I)-procollagen synthesis in vivo. alpha1(I)-procollagen and alpha2(I)-procollagen might be differentially regulated by anti-TGF-beta1 treatment. Increased TGF-beta signaling in irradiated skin fibroblasts seemed to be reversible, as shown by a reduction in PAI-1 expression after anti-TGF-beta1 treatment.

Purpose: Treatment of recurrent and progressive meningiomas remains a challenge in clinical neurooncology. This study was designed to evaluate the efficacy of the simultaneous application of 3d-conformal radiotherapy and chemotherapy with hydroxyurea (HU). Patients and methods: Twenty-one patients with recurrent or progressive meningiomas (13 benign, 4 atypical and malignant, 4 with unproven histology) received treatment by fractionated 3d-conformal radiation (55.8–59.4 Gy) and concurrent HU, administered for a median time of three months with a daily dosage of 20 mg/kg. Response was evaluated using clinical and neuro-imaging data. Results: Disease stabilization was achieved in 14/21 patients (pts). Three pts had significant improvement of tumor associated neurological symptoms with imaging criteria of minor response. Progression free survival rates 1 year and 2 years after the initiation of radio-chemotherapy were 84% and 77%, respectively. At the time of analysis a total of 6/21 pts presented with progressive disease with a median time to progression of 59 weeks. Documented radio- and chemotherapy associated toxicity was minimal; only one patient discontinued HU treatment due to gastrointestinal symptoms such as anorexia and weight loss. Conclusion: Results obtained in this study indicate that treatment with HU and simultaneous radiotherapy is safe and effective with disease stabilization in the majority of patients. Randomized trials comparing radiosurgery versus radiochemotherapy versus fractionated radiotherapy are warranted.

Purpose: In chemoradiation for pancreatic carcinoma three-dimensional target volume definitions could maximize tolerability and therapeutic effect at the same time because toxicity correlates with treatment volume. We aimed to define guidelines for elective treatment of nodal areas based on pathologic nodal involvement to optimize treatment volume for this tumor. Methods and Materials: Pathologic patterns of regional nodal spread in 175 patients who underwent primary pancreatoduodenectomy with ≥10 assessed nodes and literature data on para-aortic spread were the base of the definition of the target volume. Significant correlations between spread to lymphatic areas and tumor characteristics were determined using Fisher's exact test. Computed tomography scans and a Pinnacle 3 (Philips, Best, The Netherlands) system were used for treatment planning. Results: Among 175 resected tumors without pretreatment, 76% had regional nodal metastasis and 22% had spread to distant nodes. High-risk lymphatic areas were identified and selected for elective treatment. A standardized planning procedure was derived and tested under treatment conditions. Conclusions: Histopathologic data allowed us to develop recommendations for standardized treatment planning for ductal carcinoma of the pancreatic head. These are proposed for quality assurance in multicenter studies and routine use.

Purpose To report the results and corresponding acute and late reactions of a prospective, randomized, clinical study in locally advanced head and neck cancer comparing concurrent fluorouracil (FU) and mitomycin (MMC) chemotherapy and hyperfractionated accelerated radiation therapy (C-HART; 70.6 Gy) to hyperfractionated accelerated radiation therapy alone (HART; 77.6 Gy). Patients and Methods Three hundred eighty-four stage III (6%) and IV (94%) oropharyngeal (59.4%), hypopharyngeal (32.3%), and oral cavity (8.3%) cancer patients were randomly assigned to receive either 30 Gy (2 Gy every day) followed by 1.4 Gy bid to a total of 70.6 Gy concurrently with FU (600 mg/m2, 120 hours continuous infusion) days 1 through 5 and MMC (10 mg/m2) on days 5 and 36 (C-HART) or 14 Gy (2 Gy every day) followed by 1.4 Gy bid to a total dose of 77.6 Gy (HART). The data were analyzed on an intent-to-treat basis. Results At 5 years, the locoregional control and overall survival rates were 49.9% and 28.6% for C-HART versus 37.4% and 23.7% for HART, respectively (P = .001 and P = .023, respectively). Progression-free and freedom from metastases rates were 29.3% and 51.9% for C-HART versus 26.6% and 54.7% for HART, respectively (P = .009 and P = .575, respectively). For C-HART, maximum acute reactions of mucositis, moist desquamation, and erythema were lower than with HART, whereas no differences in late reactions and overall rates of secondary neoplasms were observed. Conclusion C-HART (70.6 Gy) is superior to dose-escalated HART (77.6 Gy) with comparable or less acute reactions and equivalent late reactions, indicating an improvement of the therapeutic ratio.

According to recent data medial location of early breast cancer was associated with a higher risk of systemic relapse and breast cancer death compared with lateral location. This paper will focus on literature data and will also present own data on the prognostic impact of radiation therapy (RT) to internal mammary nodes (IMNs) in early breast cancer patients with medial hemisphere tumor location. Four large recent series of the literature reporting on > 50,000 patients with special focus on the impact of tumor location were evaluated. No systematic RT to IMNs was applied. At the Department of Radiation Oncology, University of Erlangen, Germany, a total of 822 patients (492 with lateral and 330 with medial lesions) with early breast cancer were treated by surgery and postoperative RT with or without chemotherapy (1985–1996). All patients with medial lesions received RT to IMNs by a mixed-beam approach (50% photons, 50% electrons) with a total dose of 50 Gy. In patients with lateral lesions RT was directed to the breast alone (50.4 Gy total dose, boost 12–16 Gy). The magnitude of the negative impact of medial tumor location was relatively similar in all four studies available. According to Zucali et al., the hazard ratio (HR) for distant metastases was 1.29. The HR for breast cancer-specific survival (BCSS) varied between 1.46 (Lohrisch et al.) and 1.31 (Gaffney et al.). 5-year systemic disease-free survival (SDFS) rates were 66.3% and 74.2% for high-risk medial and lateral lesions, respectively (p < 0.005). Corresponding BCSS were 75.7% and 80.8%, respectively (p < 0.03, Lohrisch et al.). For all 822 patients following treatment on IMNs, 5-year overall survival (OS) for lateral lesions and medial lesions was 76.2% and 79.1% (n.s.), and SDFS for lateral and medial tumors 72.6% and 72.9% (n.s.), respectively. No subgroup could be identified in which prognosis of patients with medial tumors was inferior to survival data for patients with lateral lesions. In postmenopausal women, OS was significantly better for patients with medial versus lateral tumors (77.6% vs. 72.7%; p = 0.05); in patients receiving adjuvant chemotherapy SDFS (5 years) was better for those with medial versus lateral tumors (80.5% vs. 67.6%; p = 0.02). Consistent literature data exist indicating a diminished survival in patients with inner versus outer quadrant breast cancer. According to our data, RT with a total dose of 50 Gy to IMNs in breast cancer patients with medial lesions was associated with OS and SDFS rates comparable to patients with lateral tumors.

INTRODUCTION In patients with oral cancer the treatment has a strong impact on the quality of life. In recent years different therapeutic concepts have been developed, which include preoperative simultaneous 'neoadjuvant' radiochemotherapy (RCT) and one-stage surgery with tumour ablation and reconstruction. Consideration of long-term survival rates yields substantial evidence that mixed-modality treatment including neoadjuvant RCT is superior to adjuvant therapy concepts based on a surgical approach with postoperative radiation. PATIENTS AND METHODS In this nonrandomised longitudinal prospective study quality of life was evaluated in two groups made up of a total of 53 patients with squamous cell carcinoma of the oral cavity, 26 of whom underwent neoadjuvant radiochemotherapy with subsequent surgical resection while the remaining 27 received surgical treatment first and then postoperative radiotherapy. The quality-of-life core questionnaire (QLQ C-30) and the head and neck cancer module (H&N 35) of the European Organisation for Research and Treatment of Cancer (EORTC) were used. Long-term survival was estimated according to the Kaplan-Meier test. RESULTS Postoperatively both groups showed a marked reduction in quality of life, especially in restricted chewing, swallowing and speaking. One year later their quality of life had improved substantially, though without quite reaching the preoperative quality-of-life scores. Both groups showed specific impairments in the symptom scales. With adjustment for the fact that the patients were not randomised, long-term survival was 78% in the neoadjuvant treatment group and 50% in the adjuvant treatment group. CONCLUSION Temporary limitations in the quality of life can be expected after tumour treatment of the kinds presented here for oral cancer. Neoadjuvant therapy concept is more aggressive and might result in longer disease-free survival. The primary goal should be eradication of the tumour. Nevertheless preservation or reconstruction of a maximum of function is essential for a high level of quality of life. Combined-modality treatments seem to be superior to any kind of monotherapy and should therefore be preferred.

Background and purpose Wound healing disorders and the development of fibrosis following surgery in preirradiated tissue are clinically well characterised and may even become more pronounced with increasing use of neoadjuvant radiochemotherapy. The cytokine transforming growth factor beta 1 TGFβ 1 has a key role either in the wound healing process or induction of fibrosis. Following activation of the TGFβ receptors, intracellular signal transduction is mediated by a variety of Smad proteins. Smad-3 acts as an activator of signal transduction, whereas Smad-7 has an inhibitory effect. This study evaluated the biological effect of neutralizing TGFβ 1 antibodies, the relationship between TGFβ 1 and Smad-3/7 expression and changes of collagen synthesis, following inhibition of TGFβ 1 activity in irradiated rat tissue. Patients and methods A total of 45 Wistar rats (male, weight 300–450 g) were used. A free myocutaneous gracilis flap was transplanted in all rats and animals were allocated into 3 groups as follows: Group 1 ( n =15 rats) treated with surgery alone (TX); Group 2 ( n =15 rats) preoperative radiotherapy (RT) followed by TX; Group 3 ( n =15 rats) RT+TX+anti-TGFβ 1 -treatment. The interval between end of radiotherapy and grafting was 10 days. For anti-TGFβ 1 treatment, 1 μg anti-TGFβ 1 /500 μl PBS were locally applied s.c. intraoperatively and on day 1 to 7 after surgery. Tissue samples were collected perioperatively and on days 3, 7, 14, 28 following surgery from the transition area between the graft and the graft bed. ECM synthesis and expression of TGFβ 1 , Smad-3, Smad-7, prolyl-hydroxyprolinase-β were quantitated by immunohistochemistry (labelling indices). Changes in collagen synthesis were assessed qualitatively by polarisation microscopy of sirius red staining and collagen I immunhistochemistry. The different regulation of inhibitory Smad-7 was detected in irradiated and irradiated plus anti-TGFβ 1 treated animals by semiquantitative RT-PCR and the nucleocytoplasmic shuttling of phosphorylated Smad-3 was shown by isolation of nuclear proteins and Western blot analysis. Results Following anti-TGFβ 1 treatment, an attenuated expression of TGFβ 1 , a reduction in EMC synthesis and fibrosis could be observed in irradiated tissue compared to the irradiated tissue without anti-TGFβ 1 -treatment. While preoperative RT increases the expression of Smad-3/7 proteins, an upregulation of Smad-7 from day 3 until day 14 following surgery and a downregulation of Smad-3 on day 14 after surgery could be observed following anti-TGFβ 1 -treatment. The samples which were irradiated alone displayed a reduced signal for Smad-7 mRNA and an induction of Smad-3 protein phosphorylation shown by nucleocytoplasmic shuttling. In contrast, the anti-TGFβ 1 -treated samples showed an increase in Smad-7 mRNA and a downregulation of Smad-3 phosphorylation. Prolyl-hydroxyprolinase-β expression and collagen I synthesis were reduced following anti-TGFβ 1 -treatment. Conclusions A reduction of Smad-3 proteins in parallel with an increase of Smad-7 may contribute to the inhibitory effect and the reduction of ECM synthesis after blocking of TGFβ 1 activity by treatment with neutralizing antibodies. This may indicate a molecular mechanism in the therapeutic intervention to reduce fibrosis, hypertrophic scar formation and chronic wound healing disorders.