Edwin Bölke

High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: Results of a survey in EORTC institutes

OBJECTIVE Examination of the rate of grade III or grade IV radiation dermatitis during treatment of head and neck cancer (HNC) with radiotherapy (RT) and concurrent cetuximab in EORTC centres. MATERIALS AND METHOD A questionnaire was sent to all members of the EORTC Radiation Oncology Group and Head and Neck Group (111 institutions) to evaluate the widespread use of cetuximab and radiotherapy in HNC and to estimate the frequency of grades III and IV skin reactions in the radiation portals associated with this protocol. Co-morbidities, RT schedules and co-medications were also recorded. RESULTS We received responses from 28 institutions in 11 countries. A total of 125 HNC patients from 15 institutions were treated with cetuximab and concurrent RT. Information about the skin reactions was available from 71 patients. Of these 36 had no grade III/IV adverse effects in the RT field, 15 had a grade III and 20 had grade IV radiation dermatitis. No detectable relation of grades III and IV radiation dermatitis with co-morbidities such as liver insufficiency or renal dysfunction was found. CONCLUSION According to the results of the questionnaire, grade III/IV radiation dermatitis is observed in 49% of HNC patients treated with cetuximab and concurrent RT. A systematic clinical monitoring of cutaneous side effects during RT plus cetuximab is advised to ensure the safety of this protocol.

EGFr inhibitor toxicityHigh rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: Results of a survey in EORTC institutes

OBJECTIVE Examination of the rate of grade III or grade IV radiation dermatitis during treatment of head and neck cancer (HNC) with radiotherapy (RT) and concurrent cetuximab in EORTC centres. MATERIALS AND METHOD A questionnaire was sent to all members of the EORTC Radiation Oncology Group and Head and Neck Group (111 institutions) to evaluate the widespread use of cetuximab and radiotherapy in HNC and to estimate the frequency of grades III and IV skin reactions in the radiation portals associated with this protocol. Co-morbidities, RT schedules and co-medications were also recorded. RESULTS We received responses from 28 institutions in 11 countries. A total of 125 HNC patients from 15 institutions were treated with cetuximab and concurrent RT. Information about the skin reactions was available from 71 patients. Of these 36 had no grade III/IV adverse effects in the RT field, 15 had a grade III and 20 had grade IV radiation dermatitis. No detectable relation of grades III and IV radiation dermatitis with co-morbidities such as liver insufficiency or renal dysfunction was found. CONCLUSION According to the results of the questionnaire, grade III/IV radiation dermatitis is observed in 49% of HNC patients treated with cetuximab and concurrent RT. A systematic clinical monitoring of cutaneous side effects during RT plus cetuximab is advised to ensure the safety of this protocol.

Development and Management of Severe Cutaneous Side Effects in Head-and-Neck Cancer Patients during Concurrent Radiotherapy and Cetuximab

Background:The concurrent administration of cetuximab to radiotherapy has recently been shown to improve the clinical outcome of head-and-neck cancer (HNC) patients. An aggravation of the radiation-induced skin toxicity was not described. Here, however, two cases with severe skin toxicity during the combined treatment are reported.Clinical Observations:In a small group of five patients with locally advanced HNC treated with irradiation and concurrent cetuximab, two cases of unusually severe radiation dermatitis were observed. Both patients developed confluent moist desquamations confined to the irradiation field at a dose of 40 Gy (CTC [Common Toxicity Criteria] grade 3), which progressed into an ulcerative dermatitis (grade 4) at 58 Gy and 46 Gy, respectively. Histopathology showed a vacuolic degeneration of basal keratinocytes, subepidermal blister formation, and mixed perivascular and interstitial inflammatory infiltrates leading to a complete loss of the epidermis. These cutaneous side effects led to the discontinuation of radiotherapy. Topical corticosteroids and systemic antibiotic treatment resulted in wound healing, which allowed the continuation of radiotherapy.Conclusion:These findings indicate that cetuximab may have the potential to enhance the severity of radiation dermatitis in HNC patients. A systematic monitoring of cutaneous side effects during radiotherapy plus cetuximab is advised in order to reliably estimate the frequency of severe (grade 3/4) radiation dermatitis.Hintergrund:Die simultane Applikation von Cetuximab zur Strahlentherapie verbessert nach einer kürzlich publizierten Studie die Prognose von Patienten mit Kopf-Hals-Tumoren (HNC). Hinweise auf eine Verstärkung der strahlenbedingten Hautreaktion ergaben sich nicht. Im Folgenden wird allerdings über zwei Fälle mit schwersten Hautreaktionen während der kombinierten Behandlung berichtet.Beobachtungen:In einer kleinen Gruppe von fünf Patienten mit HNC, die mit Bestrahlung und simultanem Cetuximab behandelt wurden, war bei zwei Patienten eine ungewöhnlich starke Radiodermatitis zu beobachten. Beide Patienten entwickelten während der Behandlung bei einer Dosis von 40 Gy zunächst konfluierende feuchte Epitheliolysen in den Bestrahlungsfeldern (CTC [Common Toxicity Criteria] Grad 3), welche bei einer Dosis von 58 Gy bzw. 46 Gy in ulzerative Dermatitiden übergingen (CTC Grad 4). Histopathologisch zeigten sich vakuolische Degenerationen der basalen Keratinozyten, subepidermale Blasenbildungen sowie perivaskuläre und interstitielle inflammatorische Infiltrate mit komplettem Verlust der Epidermis. Diese Nebenwirkungen führten in beiden Fällen zu einer Unterbrechung der Radiotherapie. Durch eine intensive Therapie mit topischen Glukokortikosteroiden sowie eine systemische antibiotische Behandlung kam es zur kompletten Abheilung, was die Fortsetzung der Bestrahlung ermöglichte.Schlussfolgerung:Diese Beobachtungen zeigen, dass Cetuximab das Potential haben könnte, den Grad der Radiodermatitis bei Patienten mit HNC wesentlich zu verstärken. Ein systematisches Monitoring der Hautnebenwirkungen während der Radiotherapie in Kombination mit Cetuximab ist erforderlich, um die Häufigkeit der schweren Radiodermatitis (Grad 3/4) verlässlich einschätzen zu können.

Bevacizumab as a Treatment Option for Radiation-Induced Cerebral Necrosis

Radiation necrosis of normal CNS tissue represents one of the main risk factors of brain irradiation, occurring more frequently and earlier at higher total doses and higher doses per fraction. At present, it is believed that the necrosis results due to increasing capillary permeability caused by cytokine release leading to extracellular edema. This process is sustained by endothelial dysfunction, tissue hypoxia, and subsequent necrosis. Consequently, blocking the vascular endothelial growth factor (VEGF) at an early stage could be an option to reduce the development of radiation necrosis by decreasing the vascular permeability. This might help to reverse the pathological mechanisms, improve the symptoms and prevent further progression. A patient with radiationinduced necrosis was treated with an anti-VEGF antibody (bevacizumab), in whom neurologic signs and symptoms improved in accordance with a decrease in T1-weighted fluid-attenuated inversion recovery signals. Our case report together with the current literature suggests bevacizumab as a treatment option for patients with symptoms and radiological signs of cerebral necrosis induced by radiotherapy.Die strahleninduzierte Radionekrose des Gehirns stellt eine schwerwiegende Komplikation der Strahlentherapie dar und tritt bei hohen Gesamtdosen oder hohen fraktionierten Einzeldosen häufiger und früher auf. Es wird vermutet, dass hierfür eine erhöhte Freisetzung von Zytokinen ursächlich ist, die zu einer erhöhten Kapillarpermeabiliät und in der Folge zu einem extrazellulären Ödem führt. Dieser Prozess wird durch die endotheliale Dysfunktion sowie eine Gewebehypoxie weiter verstärkt und kann letztendlich zu einer Nekrose führen. Eine Blockade des vaskulären endothelialen Wachstumsfaktors (vascular endothelial growthfactor; VEGF) könnte diese verstärkte vaskuläre Permeabilität vermindern. Somit könnten pathologische Prozesse umgekehrt, neurologische Ausfallerscheinungen vermindert und ein Fortschreiten der Problematik verhindert werden. Wir präsentieren hier einen Fall einer strahleninduzierten Nekrose, bei dem sich unter Therapie mit einem anti-VEGF Antikörper (Bevacizumab) eine Besserung der neurologischen Zeichen und Symptome in Analogie zu einer MR-morphologischen Abnahme des T2-Signals zeigte. Eine Zusammenschau dieses Falles und der aktuellen verfügbaren Literatur lässt den Schluss zu, dass Bevacizumab eine Behandlungsoption für Patienten mit Symptomen und radiologischen Zeichen einer strahleninduzierten zerebralen Nekrose sein kann.

Methylated APC and GSTP1 genes in serum DNA correlate with the presence of circulating blood tumor cells and are associated with a more aggressive and advanced breast cancer disease.

BackgroundTumor-related methylated DNA and circulating tumor cells (CTC) in the peripheral blood might be of prognostic importance in breast cancer. Thus, the aim of our study was to examine free methylated DNA and CTC in the blood from breast cancer patients and to correlate it with clinicopathological features known to influence prognosis.Materials and methodsWe prospectively obtained serum samples from 85 patients with breast cancer and 22 healthy volunteers. Sera were analysed by methylation specific PCR (MethyLight PCR) for five genes: adenomatous polyposis coli (APC), ras association domain family protein 1A (RASSF1A), estrogen receptor 1 (ESR1), CDKN2A (p16) and glutathione s-transferase pi 1 (GSTP1). Beta actin (ACTB) served as control. In parallel matched peripheral blood of 63 patients was used to assay for circulating tumor cells in the peripheral blood by a modified immunomagnetic AdnaTest BreastCancerSelect with PCR detection for EPCAM, MUC1, MGB1 and SPDEF.ResultsWe found a hypermethylation in the APC gene in 29% (25/85), in RASSF1A in 26% (22/85), in GSTP1 in 18% (14/76) and in ESR1 in 38% (32/85) of all breast cancer patients. No hypermethylation of CDKN2A was found (0/25). Blood samples of patients were defined CTC positive by detecting the EPCAM 13% (8/63), MUC1 16% (10/63), MGB 9% (5/55), SPDEF 12% (7/58) and in 27% detecting one or more genes (15/55). A significant difference was seen in methylated APC DNA between cancer patients and healthy volunteers. Moreover, methylated APC, RASSF1 and CTC were significantly different in metastatic versus non-metastatic disease. In addition, the presence of methylated APC, RASSF1A and CTC correlated significantly with AJCC-staging (p = 0.001, p = 0.031 and 0.002, respectively). High incidences of methylations were found for the genes RASSF1 and ESR1 in healthy individuals (both 23% 5/22). Methylated GSTP1 was predominantly found in the serum of patients with large primaries (p = 0.023) and was highly significantly correlated with positive Her2/neu status (p = 0.003). Elevated serum CA15.3 was strongly correlated with methylated APC and CTC detection (both p = 0.000). Methylated ESR1 failed to exhibit significant correlations with any of the above mentioned parameters. The presence of CTC in peripheral blood was significantly associated with methylated APC (p = 0.012) and methylated GSTP1 (p = 0.001).ConclusionThe detection of methylated APC and GSTP1 DNA in serum correlated with the presence of CTC in the blood of breast cancer patients. Both methylated DNA and CTC correlated with a more aggressive tumor biology and advanced disease.

Evaluation of Time, Attendance of Medical Staff, and Resources During Radiotherapy for Head and Neck Cancer Patients

Introduction:A number of national and international societies have published recommendations regarding the required equipment and manpower that is assumed to be necessary to treat a specific number of patients with radiotherapy. None of these recommendations were based on actual time measurements needed for specific radiotherapy procedures. The German Society of Radiation Oncology (DEGRO) was interested in substantiating their recommendations by prospective evaluations of all important core procedures of radiotherapy in the most frequent cancer treated by radiotherapy. The results of the examinations of radiotherapy in head and neck cancer (HNC) patients are presented in this manuscript.Patients and Methods:Four radiation therapy centers (University of Jena, University of Erlangen, University of Düsseldorf and the community hospital of Neuruppin) participated in this prospective study. Working time of the different occupational groups and room occupancies for the core procedures of radiotherapy in HNC were prospectively documented during a 4-month period and subsequently statistically analyzed.Results:The time needed per patient varied considerably between individual patients and between centers for all evaluated procedures. Room occupancy, presence of technicians, and overall medical staff times were 21 min, 26 min, and 42 min, respec-tively, for planning CT with i.v. contrast medium (n = 79), and 23 min, 44 min, and 51 min respectively, for planning CT without contrast medium (n = 45). Definition of the target volume (n = 91) was the most time consuming procedure for the physicians taking 1 h 45 min on average. Medical physicists spent a mean time of 3 h 8 min on physical treatment planning (n = 97) and 1 h 8 min on authorization of the treatment plan (n = 71). Treatment simulations (n = 185) required an average room occupancy of 23 min, and a mean technicians presence of 47 min. The mean room occupancy (n = 84) was 24 min for the first radiotherapy including portal imaging associated with a mean presence of the technicians of 53 min. For routine radiotherapy sessions (n = 2,012) and routine radiotherapy sessions including portal imaging (n = 407), mean room occupancies were 13 min and 16 min, respectively. The presence of increasing number of technicians was significantly associated with shorter room occupancy. IMRT including portal imaging (n = 213) required an average room occupancy of 24 min and a mean technician time of 48 min.Conclusion:The data presented here allow an estimate of the required machine time and manpower needed for the core procedures of radiotherapy in an average head and neck cancer patient treated with a specific number of fractions. However, one has to be aware that a number of necessary and time consuming activities were not evaluated in the present study.ZusammenfassungFragestellung:Internationale Gesellschaften haben Empfehlungen für die erforderliche technische Ausrüstung und für die Anzahl von Mitarbeitern zur Behandlung von Tumorpatienten in der Strahlentherapie veröffentlicht. Keine dieser Empfehlungen basiert auf durchgeführten Messungen für die einzelnen Behandlungsabschnitte in der Strahlentherapie, sondern sind Schätzwerte. Die Deutsche Gesellschaft für Radioonkologie will ihre Empfehlungen durch prospektive Auswertungen aller wichtigen Abläufe in der Strahlentherapie bei den häufigsten Tumorentitäten untermauern. Ziel dieser Untersuchung war es, die erforderlichen Ressourcen bei der strahlentherapeutischen Behandlung von Kopf- und Halstumoren zu evaluieren.Methodik:Vier Strahlentherapie-Zentren (Universität Jena, Universität Erlangen, Universität Düsseldorf und das Städtische Krankenhaus Neuruppin) nahmen an dieser prospektiven Studie teil. Die Arbeitszeit der verschiedenen Berufsgruppen sowie die Raumbelegung bei der Planung und Durchführung der Strahlentherapie wurde prospektiv während eines Zeitraumes von 4 Monaten dokumentiert und statistisch ausgewertet.Ergebnis:Die Zeit für die einzelne Abschnitte der Behandlung variierte erheblich zwischen den einzelnen Patienten und den Behandlungszentren. Für ein CT mit Kontrastmittel (n = 79) wurden im Durchschnitt 21 Minuten für die Raumbelegungszeit benötigt. 26 Minuten benötigten die medizinisch-technischen Angestellten für die Durchführung des CTs und 42 Minuten das gesamte medizinische Personal. Für ein CT ohne Kontrastmittel (n = 45) betrug die Raumbelegungszeit 23 Minuten, 44 Minuten benötigten die m.-t. Assistenten (MTA) und 51 Minuten das gesamte medizinische Personal. Die Definition des Zielvolumens (n = 91) war das zeitaufwendigste Verfahren für das ärztliche Personal und dauerte 1 h 45 min. Die Medizin-physiker brauchten 3 h 8 min für die physikalische Bestrahlungsplanung (n = 97). Die Verifikation der Pläne durch die Ärz-te (n = 71) betrug 1h 8 min. Die Simulationen von Kopf-Hals-Tumorpatienten (n = 185) erforderten eine durchschnittliche Raumbelegungszeit von 23 min, und der Zeitaufwand für die MTA betrug 47 min. Die mittlere Raumbelegung (n = 84) betrug 24 min für die ersten Strahlentherapie einschließlich der Verifikationsaufnahme. Der zeitliche Aufwand betrug für eine MTA 53 min. Für die routinemäßige Bestrahlung von Kopf-Hals-Tumoren ohne Verifikationsaufnahme (n = 2012) waren 13 Minuten erforderlich, mit Verifikationsaufnahmen (n = 407) 16 min. Die Anwesenheit von mehreren MTAs korrelierte signifikant mit einer kürzeren Raumbelegungszeit (p < 0,05). Die intensitätsmodulierte Radiotherapie mit Verifikation (n = 213) erforderte eine durchschnittliche Raumbelegungszeit von 24 min mit der Anwesenheit einer MTA von 48 min.Schlussfolgerung:Die Untersuchung ermöglicht die Abschätzung des durchschnittlichen Personal- und Ressourcenbedarf für die Kernprozeduren einer Strahlentherapie bei Patienten mit Kopf-Hals-Tumoren, die mit einer bestimmten Anzahl von Fraktionen behandelt werden. Dabei ist zu beachten, dass eine Reihe von erforderlichen und zeitaufwendigen Tätigkeiten in der Studie nicht evaluiert wurden.

Preoperative oral application of immunoglobulin-enriched colostrum milk and mediator response during abdominal surgery.

Our objective was to evaluate the influence of pre-operative oral application of an immunoglobulin-enriched milk preparation on endotoxin translocation and mediator release during and after abdominal surgery. Forty patients who had been treated by partial (n = 4) or total gastrectomy (n = 8) or pancreatic resection (n = 28) were enrolled in a placebo-controlled pilot study. Pre-operatively, patients were randomly treated for 3 days by oral application of a bovine milk preparation (lactobin® 56g/day, n = 20) or placebo (n = 20). In both groups, endotoxin translocation and mediator release was studied pre- and intraoperatively by measuring endotoxin, endotoxin-neutralizing capacity (ENC), interleukin 6, C-reactive protein, transferrin, &agr;-2-macroglobulin, albumin, apoliprotein-A1/-B, IgG, IgA, and IgM. The clinical course was followed up by daily evaluation of the Apache-II-score. Clinical data were comparable in both groups. The lactobin group showed significantly lower levels of endotoxin and ENC compared to the placebo group. Acute phase response, endotoxin-binding proteins, and clinical outcome did not differ between both groups. We conclude that prophylactic oral application of lactobin reduces perioperative endotoxemia and prevents reduction of ENC, suggesting a stabilization of gut barrier during abdominal surgery.

Glioblastoma Multiforme Metastasis Outside the CNS: Three Case Reports and Possible Mechanisms of Escape

Introduction Primary brain and CNS tumor incidence is approximately 19 per 100,000 individuals per year in the United States compared with seven per 100,000 individuals worldwide. Worldwide this accounts for 2% of all primary tumors and 7% of years of life lost from cancer before the age of 70 years. Glioblastoma multiforme (GBM) is also the most aggressive brain tumor with poor prognosis; patients with GBM have a median survival time of about 14 months. GBM metastases outside the CNS are rare, so therapeutic experience with these types of tumors is limited. Normally the brain is immunologically and anatomically separated from the body by the blood brain barrier. Herein, we present the cases of three patients with GBM with extra-CNS metastasis. The variety of metastasis locations demonstrated in these cases helps to illustrate the various mechanism and corresponding risk factors that allow GBM to escape the CNS.

Bendamustine in patients with relapsed or refractory multiple myeloma

ObjectiveIn patients with multiple myeloma, bendamustine monotherapy is effective as 1st and 2nd line therapy. However, data for patients with advanced multiple myeloma is rare.MethodsIn this retrospective analysis we have identified 39 patients with relapsed or refractory multiple myeloma by means of case research, who have been treated at our institution with bendamustine as salvage therapy. After in median 2 lines of prior therapy (range:1-5) patients received in median 3 (range: 1-10) cycles of bendamustine. Bendamustine dosage was 80-150 mg on day 1+2 of a monthly cycle. Bendamustine was administered as monotherapy in 39% of patients, whereas 61% received concomitant steroids.ResultsToxicity was mild to moderate. Response rates were as follows: 3% vgPR, 33% PR, 18% MR, 26% SD and 20% PD. The median event-free and overall survival were 7 and 17 months, respectively.ConclusionsIn conclusion, in patients with advanced multiple myeloma bendamustine is effective and associated with mild toxicity. Therefore, the role of bendamustine in patients with multiple myeloma should be investigated in further clinical trials.

Inflammatory response during abdominal and thyroid surgery: a prospective clinical trial on mediator release.

Several studies have been demonstrated that endotoxin is a potent stimulus of the acute inflammatory response following traumatic injury. Although numerous studies have indicated that the extent of surgical intervention correlates well with the inflammatory response, the potential role of endotoxin as a trigger under those conditions still remains unknown. Therefore, the aim of this study was to elucidate whether or not the up-regulated inflammatory mediators are paralleled by increased endotoxin plasma levels during and following surgery, and whether the extent of surgical intervention represents a crucial factor under those conditions. To study this, plasma was collected at various time points during and after surgery from 52 patients subjected to abdominal surgery (i.e., major surgery) and 25 patients subjected to thyroid surgery (i.e., minor surgery). Plasma was assessed for endotoxin, endotoxin neutralizing capacity (ENC), and inflammatory mediators (leucotriene-C4 [LTC4]-, 6-keto-prostaglandin-F-1-alpha [PGF]-, thromboxane-B2 [TxB2], interleukin-6 [IL-6], and C-reactive protein [CRP]). Furthermore, splanchnic blood circulation was measured by determination of the intraluminal pH of the stomach and sigma (pHi) by intraluminal tonometry. Mesenteric lymph nodes were also collected at the time point of organ mobilization in the major surgery group and were assessed for bacterial translocation. Among all parameters investigated, endotoxin showed the most rapid changes. A significant increase in plasma levels of endotoxin and a decrease of ENC were found in the major surgery groups following induction of anesthesia and in the minor surgery groups after skin incision. Moreover, the incidence of elevated endotoxin levels was significantly higher (89% with elevated endotoxin levels) than the incidence of bacterial translocation (35% with gram-negative bacteria) in mesenterial lymph nodes of the major surgery group. pHi decreased significantly in both groups after skin incision, but no difference was observed between the major and minor surgery groups. Plasma mediators of the arachidonic acid cascade (LTC4, PGF, and TxB2) were only elevated in individual patients during and following surgery in both groups. Conversely, the post-operative increase in the acute phase mediators was significantly different in the major and minor surgery groups. IL-6 plasma levels peaked higher and earlier after major surgery than after minor surgery and the delayed increase of CRP was significantly greater in the major surgery group. In conclusion, the results indicate that plasma levels of endotoxin significantly correlate with the severity of the surgical intervention and may play an important role in inducing mediators of the acute phase reaction under such conditions.