Robert Michael Hermann

Multicenter Phase II Trial of Chemoradiation With Oxaliplatin for Rectal Cancer

PURPOSE To evaluate the activity and safety of preoperative radiotherapy (RT) and concurrent capecitabine and oxaliplatin (XELOX-RT) plus four cycles of adjuvant XELOX in patients with rectal cancer. PATIENTS AND METHODS One hundred ten patients with T3/T4 or N+ rectal cancer were entered onto the trial in 11 investigator sites and received preoperative RT (50.4 Gy in 28 fractions). Capecitabine was administered concurrently at 1,650 mg/m2 on days 1 to 14 and 22 to 35, and oxaliplatin was administered at 50 mg/m2 on days 1, 8, 22, and 29. Surgery was scheduled 4 to 6 weeks after completion of XELOX-RT. Four cycles of adjuvant XELOX (capecitabine 1,000 mg/m2 bid on days 1 to 14; oxaliplatin 130 mg/m2 on day 1) were administered. The main end points were activity as assessed by the pathologic complete response (pCR) rate and the feasibility of postoperative XELOX chemotherapy. RESULTS After XELOX-RT, 103 of 104 eligible patients underwent surgery; pCR was achieved in 17 patients (16%), one patient had ypT0N1 disease, and 53 patients showed tumor regression of more than 50% of the tumor mass. R0 resections were achieved in 95% of patients, and sphincter preservation was accomplished in 77%. Full-dose preoperative XELOX-RT was administered in 96%. Grade 3 or 4 diarrhea occurred in 12% of patients. Postoperative complication occurred in 43% of patients. Sixty percent of patients received all four cycles of adjuvant XELOX, with sensory neuropathy (18%) and diarrhea (12%) being the main grade 3 or 4 toxicities. CONCLUSION Preoperative XELOX-RT plus four cycles of adjuvant XELOX is an active and feasible treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based treatment with XELOX- based multimodality treatment.

The delineation of target volumes for radiotherapy of lung cancer patients.

PURPOSE Differences in the delineation of the gross target volume (GTV) and planning target volume (PTV) in patients with non-small-cell lung cancer are considerable. The focus of this work is on the analysis of observer-related reasons while controlling for other variables. METHODS In three consecutive patients, eighteen physicians from fourteen different departments delineated the GTV and PTV in CT-slices using a detailed instruction for target delineation. Differences in the volumes, the delineated anatomic lymph node compartments and differences in every delineated pixel of the contoured volumes in the CT-slices (pixel-by-pixel-analysis) were evaluated for different groups: ten radiation oncologists from ten departments (ROs), four haematologic oncologists and chest physicians from four departments (HOs) and five radiation oncologists from one department (RO1D). RESULTS Agreement (overlap > or = 70% of the contoured pixels) for the GTV and PTV delineation was found in 16.3% and 23.7% (ROs), 30.4% and 38.6% (HOs) and 32.8% and 35.9% (RO1D), respectively. CONCLUSION A large interobserver variability in the PTV and much more in the GTV delineation were observed in spite of a detailed instruction for delineation. The variability was smallest for group ROID where due to repeated discussions and uniform teaching a better agreement was achieved.

Effect of Pentoxifylline and Tocopherol on Radiation Proctitis/Enteritis

Background and Purpose:Chronic radiation proctitis/enteritis is a relevant complication of pelvic irradiation, which is still mainly treated by supportive measures only. There is some evidence that the combined treatment with pentoxifylline and tocopherol might alter the pathogenesis of radiation-induced fibrosis. In a retrospective analysis the clinical benefit of the treatment with pentoxifylline/tocopherol on radiation-induced proctitis/enteritis was evaluated, compared to supportive care only.Patients and Methods:Of 30 patients with radiation-induced proctitis/enteritis grade I–II according to the RTOG/EORTC toxicity criteria, 21 were treated with pentoxifylline and tocopherol. Depending on physician’s decision nine patients received symptomatic treatment only.Results:With pentoxifylline/tocopherol treatment 15/21 patients (71%) experienced a relief of their symptoms. A reduction from grade I/II to grade 0 toxicity was observed in seven and from grade II to grade I toxicity in eight patients. No improvement was seen in six patients. The median time to improvement with pentoxifylline and tocopherol treatment was 28 weeks. In three of nine patients who were treated supportively only, deterioration of symptoms occurred. Three patients experienced no amelioration, and three patients with grade I toxicity experienced a spontaneous relief of their symptoms (33%).Conclusion:The combination treatment with pentoxifylline and tocopherol seems to have a benefit in patients with grade I–II radiation-induced proctitis/enteritis. The optimal schedule of treatment duration is not yet clear. From the observations made in this study it is assumed the treatment should be given for 6–12 months at least. A prospective phase II study should be undertaken to evaluate optimal treatment duration.Hintergrund und Ziel:Die strahleninduzierte chronische Proktitis/Enteritis ist eine relevante Komplikation nach Beckenbestrahlungen, die hauptsächlich symptomatisch therapiert wird. Die kombinierte Behandlung mit Pentoxifyllin und Tocopherol könnte die Pathogenese der strahleninduzierten Fibrose beeinflussen. In einer retrospektiven Analyse wurde der klinische Nutzen dieser Kombinationstherapie bei strahleninduzierter Proktitis/Enteritis ausgewertet und mit alleiniger symptomatischer Behandlung verglichen.Patienten und Methodik:Von 30 Patienten mit einer strahleninduzierten Proktitis/Enteritis Grad I–II nach den Kriterien der RTOG/EORTC wurden 21 mit Pentoxifyllin und Tocopherol behandelt. In Abhängigkeit von der ärztlichen Entscheidung wurden neun Patienten nur symptomatisch behandelt (Tabelle 1).Ergebnisse:15/21 Patienten (71%) unter Therapie mit Pentoxifyllin und Tocopherol erlebten eine Verbesserung ihrer Symptome (Tabelle 3, Abbildung 1). Eine Reduktion von Grad I/II zu Grad 0 trat bei sieben, von Grad II zu I bei acht Patienten auf. Keine Verbesserung konnte bei sechs Patienten erreicht werden. Die mittlere Zeit bis zur Verbesserung der Symptome unter Therapie mit Pentoxifyllin und Tocopherol betrug 28 Wochen (7 Monate) (Abbildung 3). Drei der neun symptomatisch therapierten Patienten erlitten eine Symptomverschlechterung. Drei Patienten erlebten keine Befundänderung, und drei Patienten mit Grad-I-Toxizität erfuhren eine spontane Verbesserung ihrer Symptome (33%) (Tabelle 4).Schlussfolgerung:Die Kombinationstherapie aus Pentoxifyllin und Tocopherol scheint einen Nutzen bei der strahleninduzierten Proktitis/Enteritis Grad I–II zu haben (Abbildung 2). Die optimale Behandlungsdauer ist nicht bekannt. Nach den Ergebnissen dieser Studie ist anzunehmen, dass die Medikamente mindestens 6–12 Monate gegeben werden sollten. Eine prospektive Phase- II-Studie sollte durchgeführt werden, um die optimale Behandlungsdauer zu evaluieren.

Organ function and quality of life after transoral laser microsurgery and adjuvant radiotherapy for locally advanced laryngeal cancer.

Background and Purpose:Transoral laser microsurgery (TLM) and adjuvant radiotherapy are an established therapy regimen for locally advanced laryngeal cancer at our institution. Aim of the present study was to assess value of quality of life (QoL) data with special regard to organ function under consideration of treatment efficacy in patients with locally advanced laryngeal cancer treated with larynx-preserving TLM and adjuvant radiotherapy.Patients and Methods:From 1994 to 2006, 39 patients (ten UICC stage III, 29 UICC stage IVA/B) with locally advanced laryngeal carcinomas were treated with TLM and adjuvant radiotherapy. Data concerning treatment efficacy, QoL (using the VHI [Voice Handicap Index], the EORTC QLQ-C30 and QLQ-H&N35 questionnaires) and organ function (respiration, deglutition, voice quality) were obtained for ten patients still alive after long-term follow-up. Correlations were determined using the Spearman rank test.Results:After a median follow-up of 80.8 months, the 5-year overall survival rate was 46.8% and the locoregional control rate 76.5%, respectively. The larynx preservation rate was 89.7% for all patients and 100% for patients still alive after follow-up. Despite some verifiable problems in respiration, speech and swallowing, patients showed a subjectively good QoL.Conclusion:TLM and adjuvant radiotherapy is a curative option for patients with locally advanced laryngeal cancer and an alternative to radical surgery. Even if functional deficits are unavoidable in the treatment of locally advanced laryngeal carcinomas, larynx preservation is associated with a subjectively good QoL.Hintergrund und Ziel:Lasermikrochirurgie und adjuvante Strahlentherapie sind in der Klinik der Autoren etablierte Behandlungsmethoden lokal fortgeschrittener Larynxkarzinome mit guten onkologischen Ergebnissen und einer hohe Rate an Organerhalt. Bei organerhaltender Therapie sind funktionelle Einschränkungen oft unvermeidbar. Neben den onkologischen Ergebnissen sollten in dieser Studie das objektive Ausmaß solcher Einschränkungen und deren subjektive Wertung durch die Patienten untersucht werden.Patienten und Methodik:Von 1994 bis 2006 wurden 39 Patienten (zehn UICC-Stadium III, 29 UICC-Stadium IVA/B) mit lokal fortgeschrittenen Larynxkarzinomen mittels Lasermikrochirurgie und adjuvanter Strahlentherapie behandelt. Bei zehn Patienten erfolgte im Rahmen der Nachsorge in den Jahren 2006/2007 eine Erhebung von Lebensqualitätsdaten. Die Schluckfunktion wurde flexibel endoskopisch überprüft, die Atmung durch eine Bodyplethysmographie. Die Objektivierung der Stimmqualität erfolgte durch das Göttinger Heiserkeitsdiagramm.Ergebnisse:Nach einer medianen Beobachtungsdauer von 80,8 Monaten betrugen die 5-Jahres-Überlebensrate 46,8% und die lokoregionale Kontrollrate 76,5%. Eine Salvage-Laryngektomie bei Lokalrezidiv erhielten vier Patienten, so dass im Verlauf eine 89,7%ige Rate an Larynxerhalt erreicht werden konnte. Bei der objektiven Untersuchung der Funktionseinschränkungen zeigte sich bei fünf Patienten eine gelegentliche Aspiration bei kräftigem Hustenreflex. Die übrigen fünf Patienten wiesen keine Schluckstörung auf. Eine Normalstimme lag bei keinem Patienten vor. Es bestand jedoch keine signifikante Korrelation der objektivierten Funktionsstörungen mit den Lebensqualitätsfunktionsskalen: Subjektiv schätzen die Patienten ihre Lebensqualität als gut ein.Schlussfolgerung:Lasermikrochirurgie und adjuvante Strahlentherapie sind eine Therapieoption für lokal fortgeschrittene Larynxkarzinome, die neben guten onkologischen Ergebnissen eine hohe Rate an Organerhalt ermöglicht. Die Patienten schätzen ihre Lebensqualität im weiteren Verlauf subjektiv als gut ein. Die tatsächlichen funktionellen Einschränkungen werden durch die Lebensqualitätsdaten allerdings nicht sicher abgebildet. Daher ist zur objektiven Beurteilung posttherapeutischer Funktionsergebnisse die klinische Erhebung funktioneller Befunde erforderlich.

Identification of Genes Responsive to Gamma Radiation in Rat Hepatocytes and Rat Liver by cDNA Array Gene Expression Analysis

Abstract Christiansen, H., Batusic, D., Saile, B., Hermann, R. M., Dudas, J., Rave-Frank, M., Hess, C. F., Schmidberger, H. and Ramadori, G. Identification of Genes Responsive to Gamma Radiation in Rat Hepatocytes and Rat Liver by cDNA Array Gene Expression Analysis. Radiat. Res. 165, 318–325 (2006). The mechanisms underlying hepatocellular damage after irradiation are obscure. We identified genes induced by radiation in isolated rat hepatocytes in vitro by cDNA array gene expression analysis and then screened in vivo experiments with those same genes using real-time PCR and Western blotting. Hepatocytes were irradiated and cDNA array analyses were performed 6 h after irradiation. The mRNA of differentially expressed genes was quantitatively analyzed by real-time PCR. cDNA array analyses showed an up-regulation of 10 genes in hepatocytes 6 h after irradiation; this was confirmed by real-time PCR. In vivo, rat livers were irradiated selectively. Treated and sham-irradiated controls were killed humanely 1, 3, 6, 12, 24 and 48 h after irradiation. Liver RNA was analyzed by real-time PCR; expression of in vivo altered genes was also analyzed at the protein level by Western blotting. Up-regulation was confirmed for three of the in vitro altered genes (multidrug resistance protein, proteasome component C3, eukaryotic translation initiation factor 2). Histologically, livers from irradiated animals were characterized by steatosis of hepatocytes. Thus we identified genes that may be involved in liver steatosis after irradiation. The methods shown in this work should help to further clarify the consequences of radiation exposure in the liver.

Prognostic Value of Hemoglobin Concentrations in Patients with Advanced Head and Neck Cancer Treated with Combined Radio-Chemotherapy and Surgery

Purpose: Hemoglobin levels are currently the focus of interest as prognostic factors in patients with head and neck cancer. Most published clinical trials have confirmed hemoglobin to possess a significant influence on survival in patients treated with radiotherapy. In our study we have investigated the prognostic value of hemoglobin in a combined modality schedule. Patients and Methods: Forty-three patients with advanced head and neck tumors were treated with combined radio-chemotherapy. The therapy comprised 2 courses of induction chemotherapy with ifosfamide (1,500 mg/m2, day 1 to 5) and cisplatin (60 mg/m2, day 5) followed by hyperfractionated accelerated radiotherapy with a total dose of only 30 Gy. Surgery involved tumor resection and neck dissection. Results: The 1-year overall survival rate and the 2-year survival rate were 79% and 56%, respectively. The 1- and 2-year recurrence-free survival rates were 68% and 49%, respectively. Prognostic factors with an impact on survival were seen in tumor size (T3 vs T4, p = 0.0088), response to radio-chemotherapy at the primary site (no vital tumor rest vs vital tumor rest, p = 0.045), response to lymph node radio-chemotherapy (no vital tumor cells vs vital tumor cells, p = 0.013) and level of hemoglobin after radio-chemotherapy (Hb ≥ 11.5 g/dl vs < 11.5 g/dl, p = 0.0084). Conclusion: In our study hemoglobin level after radio-chemotherapy was identified for the first time to be also a significant prognostic factor (univariate analysis) in head and neck cancer patients who underwent combined radio-chemotherapy. Besides chemotherapy plus low-dose irradiation achieved similar results in comparison with radical resection and high-dose radiotherapy at least for the first 2 years after therapy. Relapsing disease could be treated with 1 additional course of radiotherapy which is supposed to be well tolerated.Hintergrund: Hämoglobinkonzentrationen sind in der letzten Zeit, insbesondere bei Patienten mit Kopf-Hals-Tumoren, als Prognosefaktor in den Mittelpunkt des Interesses gerückt. Die meisten klinischen Studien zeigen einen signifikanten Einfluß der Hämoglobinkonzentration auf das Überleben der Patienten unter Radiotherapie. In unserer Studie haben wir den Einfluß des Hämoglobins in einem multimodalen Regime getestet. Patienten und Methoden: 43 Patienten mit fortgeschrittenen Kopf-Hals-Tumoren wurden mit kombinierter Radiochemotherapie behandelt. Die Therapie bestand aus zwei Induktionskursen mit Ifosfamid (1 500 mg/m2, Tag 1 bis 5) und Cisplatin (60 mg/m2, Tag 5), gefolgt von einer hyperfraktioniert akzelerierten Radiatio mit einer Gesamtherddosis von nur 30 Gy. Anschließend erfolgte die radikale Operation mit Neck-Dissection. Ergebnisse: Die Ein- und Zwei-Jahres-Überlebensraten betrugen 79% bzw. 56%, die entsprechenden rezidivfreien Überlebensraten für ein und zwei Jahre 68% und 49%. In unserer Studie waren Tumorgröße (T3 vs. T4, p = 0,0088), Ansprechen auf die Radiochemotherapie am Tumor (histologische Tumorfreiheit vs. Tumorreste, p = 0,045), Ansprechen der Radiochemotherapie im Bereich der Lymphknoten (histologische Tumorfreiheit vs. Tumorreste, p = 0,013) und der Hämoglobinwert nach Radiochemotherapie von prognostischer Bedeutung (Hämoglobin ≥ 11,5 g/dl vs. < 11,5 g/dl, p = 0,0084). Schlußfolgerung: In unserer Studie besaß Hämoglobin einen signifikanten prognostischen Einfluß auf das Überleben bei Patienten mit Kopf-Hals-Tumoren, die einer kombinierten Radiochemotherapie unterzogen wurden (univariate Analyse). Des weiteren konnte demonstriert werden, daß die Chemotherapie und eine anschließende Strahlenbehandlung mit geringer Gesamtdosis ähnliche Ergebnisse erbringen im Vergleich zu radikaler Resektion und hochdosierter Radiotherapie. Im Falle eines Rezidivs könnte dem Patienten noch ein voller Kurs reiner Strahlentherapie zugemutet werden.

A disease-specific enteral nutrition formula improves nutritional status and functional performance in patients with head and neck and esophageal cancer undergoing chemoradiotherapy: Results of a randomized, controlled, multicenter trial

In patients with head and neck and esophageal tumors, nutritional status may deteriorate during concurrent chemoradiotherapy (CRT). The aim of this study was to investigate the influence of enteral nutrition enriched with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on body composition and nutritional and functional status.

High-Grade Acute Organ Toxicity During Preoperative Radiochemotherapy as Positive Predictor for Complete Histopathologic Tumor Regression in Multimodal Treatment of Locally Advanced Rectal Cancer*

Purpose:To test for a possible correlation between high-grade acute organ toxicity during preoperative radiochemotherapy and complete tumor regression after total mesorectal excision in multimodal treatment of locally advanced rectal cancer.Patients and Methods:From 2001 to 2008, 120 patients were treated. Preoperative treatment consisted of normofractionated radiotherapy at a total dose of 50.4 Gy, and either two cycles of 5-fluorouracil (5-FU) or two cycles of 5-FU and oxaliplatin. Toxicity during treatment was monitored weekly, and any toxicity CTC (Common Toxicity Criteria) ≥ grade 2 of enteritis, proctitis or cystitis was assessed as high-grade organ toxicity for later analysis. Complete histopathologic tumor regression (TRG4) was defined as the absence of any viable tumor cells.Results:A significant coherency between high-grade acute organ toxicity and complete histopathologic tumor regression was found, which was independent of other factors like the preoperative chemotherapy schedule. The probability of patients with acute organ toxicity ≥ grade 2 to achieve TRG4 after neoadjuvant treatment was more than three times higher than for patients without toxicity (odds ratio: 3.29, 95% confidence interval: [1.01, 10.96]).Conclusion:Acute organ toxicity during preoperative radiochemotherapy in rectal cancer could be an early predictor of treatment response in terms of complete tumor regression. Its possible impact on local control and survival is under further prospective evaluation by the authors’ working group.Ziel:Überprüfung einer möglichen Korrelation zwischen höhergradiger akuter Organtoxizität während präoperativer Radiochemotherapie und kompletter Tumorregression nach totaler mesorektaler Exzision in der multimodalen Behandlung von lokal fortgeschrittenen Rektumkarzinomen.Patienten und Methodik:Im Zeitraum von 2001 bis 2008 wurden 120 Patienten behandelt. Die präoperative Behandlung bestand aus einer normofraktionierten Radiotherapie mit einer Gesamtdosis von 50,4 Gy und entweder zwei Zyklen 5-Fluorouracil (5-FU) oder zwei Zyklen 5-FU und Oxaliplatin. Die Toxizität während der Behandlung wurde wöchentlich untersucht. Jede Toxizität ≥ Grad 2 nach CTC (Common Toxicity Criteria) in Form von Enteritis, Proktitis oder Zystitis wurde dabei als höhergradige Organtoxizität gewertet und für spätere Analysen verwendet. Bei vollständigem histopathologischen Tumoransprechen (TRG4) konnten im Operationspräparat nach neoadjuvanter Therapie keine vitalen Tumorzellen mehr identifiziert werden.Ergebnisse:Es fand sich eine signifikante Korrelation zwischen höhergradiger akuter Organtoxizität und kompletter Tumorregression, und zwar in multivariater Analyse unabhängig von anderen Faktoren wie z.B. dem präoperativen Chemotherapieregime. Die Wahrscheinlichkeit für die Patienten mit höhergradigen Nebenwirkungen, eine histopathologische Komplettremission zu entwickeln, war mehr als dreimal höher als für Patienten ohne Toxizität (Odds-Ratio: 3,29, 95%-Konfidenzintervall: [1,01, 10,96]).Schlussfolgerung:Höhergradige akute Organtoxizität während präoperativer Radiochemotherapie bei Patienten mit multimodaler Therapie lokal fortgeschrittener Rektumkarzinome könnte einen frühen Prädiktor für das Ansprechen auf die Therapie in Bezug auf die histopathologische Remission darstellen. Ob dieser Parameter auch für die lokale Kontrolle sowie das Gesamtüberleben prädiktiv sein kann, wird in weiteren prospektiven Untersuchungen durch die Arbeitsgruppe der Autoren untersucht.

Effect of Radiation on Gene Expression of Rat Liver Chemokines: In Vivo and In Vitro Studies

Abstract Moriconi, F., Christiansen, H., Raddatz, D., Dudas, J., Hermann, R. M., Rave-Fränk, M., Sheikh, N., Saile, B., Hess, C. F. and Ramadori, G. Effect of Radiation on Gene Expression of Rat Liver Chemokines: In Vivo and In Vitro Studies. Radiat. Res. 169, 162–169 (2008). The aim of the study was to analyze the effect of a single irradiation on chemokine gene expression in the rat liver and in isolated rat hepatocytes. RNA extracted from livers and from hepatocytes within the first 48 h after irradiation was analyzed by real-time PCR and the Northern blot assay. The chemokine concentrations in the serum of irradiated rats were measured quantitatively by ELISA. A significant radiation-induced increase of CINC1, IP10, MCP1, MIP3α, MIP3β, MIG and ITAC gene expression could be detected at the RNA level in the liver. CINC1, MCP1 and IP10 serum levels were significantly increased. In rat hepatocytes in vitro, only MIP3α showed a radiation-induced increase in expression, while CINC1, IP10, MIP3β, MIG, MIP1α, ITAC and SDF1 RNA levels were significantly down-regulated. However, incubation of irradiated hepatocytes in vitro with either TNF-α, IL1β, or IL6 plus TNF-α led to up-regulation of MCP1, IP10 and MCP1 or CINC1 and MIP3β, respectively. Irradiation of the liver induces up-regulation of the genes of the main proinflammatory chemokines, probably through the action of locally synthesized proinflammatory cytokines. The reason for the lack of liver inflammation in this model has still to be clarified.

Irradiation as preparative regimen for hepatocyte transplantation causes prolonged cell cycle block.

Purpose: Hepatocyte transplantation following liver irradiation (IR) and partial hepatectomy (PH) leads to extensive liver repopulation. We investigated the changes in the liver induced by IR explaining the loss of reproductive integrity in endogenous hepatocytes. Materials and methods: Right lobules of rat liver underwent external beam IR (25 Gy). A second group was subjected to additional 33% PH of the untreated left liver lobule. Liver specimens and controls were analyzed for DNA damage, apoptosis, proliferation and cell cycle related genes (1 hour to up to 12 weeks). Results: Double strand breaks (phosphorylated histone H2AX) induced by IR rapidly declined within hours and were no longer detectable after 4 days. No significant apoptosis was noted and steady mRNA levels (B-cell lymphoma 2-associated X protein (BAX), caspase 3 and 9) were in line with the lack of DNA fragmentation. However, gene expression of p53 and p21 in irradiated liver tissue increased. Transcripts of cyclin D1, proliferating cell nuclear antigen (PCNA), and cyclin B augmented progressively, whereas cyclin E was only affected moderately. Following PH, irradiated livers displayed persistently high protein levels of p21 and cyclin D1. However, cell divisions were infrequent, as reflected by low PCNA levels up to four weeks. Conclusion: IR leads to a major arrest in the G1/S phase and to a lesser extent in the G2/M transition of the cell cycle, resulting in reduced regenerative response following PH. The persistent block of at least four weeks may promote preferential proliferation of transplanted hepatocytes in this milieu.