Hans Christiansen

Organ Preserving Transoral Laser Microsurgery for Cancer of the Hypopharynx

Objective: To assess the feasibility of transoral laser microsurgery (TLM) in the treatment of hypopharyngeal cancer, with a special focus on piriform sinus carcinomas, and to report the oncologic and functional outcomes.

Radiotherapy of malignant gliomas: Comparison of volumetric single arc technique (RapidArc), dynamic intensity-modulated technique and 3D conformal technique

PURPOSE The analysis was designed to identify the optimal radiation technique for patients with malignant glioma. METHODS A volumetric-modulated radiation treatment technique (RapidArc), an IMRT technique and a 3D conformal technique were calculated on computed tomograms of 14 consecutive patients with malignant glioma. The treatment plans were compared with each other using dose-volume histograms. RESULTS The 3D conformal technique showed a good PTV coverage, if PTV was distant to organs at risk (OAR). If PTV was nearby OAR, the 3D technique revealed a poor PTV coverage in contrast to both intensity-modulated techniques. The conventional IMRT technique showed a slightly better PTV coverage than RapidArc. The advantages of RapidArc were a shorter treatment time, less monitor units and a small V(107%). CONCLUSIONS If PTV is distant to OAR, the use of 3D conformal technique is sufficient. Otherwise an intensity-modulated technique should be used. RapidArc was faster than conventional IMRT and should be preferred if PTV coverage is adequate.

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.

High-grade acute organ toxicity as positive prognostic factor in primary radio(chemo)therapy for locally advanced, inoperable head and neck cancer.

Purpose:To test for a possible correlation between high-grade acute organ toxicity during primary radio(chemo)therapy and treatment outcome in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).Patients and Methods:From 05/1994 to 01/2009, 216 HNSCC patients were treated with radio(chemo)therapy in primary approach. They received normofractionated (2 Gy/fraction) irradiation including associated nodal drainage sites to a cumulative dose of 70 Gy. 151 patients received additional concomitant chemotherapy (111 patients 5-fluorouracil/mitomycin C, 40 patients cisplatin-based). Toxicity during treatment was monitored weekly according to the Common Toxicity Criteria (CTC), and any toxicity grade CTC ≥ 3 of mucositis, dysphagia or skin reaction was assessed as high-grade acute organ toxicity for later analysis.Results:A statistically significant coherency between high-grade acute organ toxicity and overall survival as well as locoregional control was found: patients with CTC ≥ 3 acute organ toxicity had a 5-year overall survival rate of 44% compared to 8% in patients without (p < 0.01). Thereby, multivariate analyses revealed that the correlation was independent of other possible prognostic factors or factors that may influence treatment toxicity, especially concomitant chemotherapy and radiotherapy technique or treatment-planning procedure.Conclusion:These data indicate that normal tissue and tumor tissue may behave similarly with respect to treatment response, as high-grade acute organ toxicity during radio(chemo)therapy showed to be an independent prognostic marker in the own patient population. However, the authors are aware of the fact that a multivariate analysis in a retrospective study generally has statistical limitations. Therefore, their hypothesis should be further analyzed on biomolecular and clinical levels and other tumor entities in prospective trials.ZusammenfassungHintergrund und Ziel:Nach primärer Radio(chemo)therapie lokal fortgeschrittener Kopf-Hals-Tumoren kommt es bei einigen Patienten zu einer kompletten Remission, bei anderen lediglich zu einer partiellen Remission mit frühem Rezidiv. Unterschiedlich ist auch die Strahlenempfindlichkeit des Normalgewebes: Einige Patienten zeigen starke, andere hingegen weniger intensive Akutreaktionen. Im Rahmen dieser Arbeit wurde geprüft, ob Patienten, die höhergradige Akutreaktionen entwickeln, im Vergleich zu Patienten, bei denen diese nicht auftreten, eine bessere Prognose haben.Patienten und Methodik:Von 1994 bis 2009 wurden 216 Patienten mit lokal fortgeschrittenen Plattenepithelkarzinomen im Kopf-Hals-Bereich in der eigenen Klinik primär radiotherapiert (70 Gy). 151 Patienten erhielten begleitend eine Chemotherapie (111 Patienten 5-Fluorouracil/Mitomycin C, 40 Patienten Cisplatin-basiert). Jede Akuttoxizität ≥ Grad 3 in Form von Hautreaktion, Mukositis oder Dysphagie wurde als höhergradige akute Organtoxizität gewertet. Akuttoxizität ≥ Grad 3 wurde vor Beginn der Analyse als „cutoff value“ gewählt, da es ab dieser Toxizität zu einer signifikanten Einschränkung der Lebensqualität der Patienten kommt.Ergebnisse:Das Gesamtüberleben sowie die lokoregionäre Kontrolle nach 5 Jahren betrugen 18% bzw. 63%. Es fand sich dabei eine statistisch signifikante Korrelation zwischen höhergradiger akuter Organtoxizität und der Prognose: In der Gruppe der Patienten mit höhergradiger akuter Organtoxizität betrugen das Gesamtüberleben und die lokale Kontrolle nach 5 Jahren 44% und 74% im Vergleich zu 8% und 56% bei den Patienten ohne akute höhergradige Nebenwirkungen (p < 0,01, p = 0,04). Diese Korrelation war in multivariater Analyse statistisch unabhängig von anderen Faktoren, die möglicherweise die Toxizität beeinflussen, wie begleitende Chemotherapie oder Strahlentherapieplanung (konventionell/dreidimensional).Schlussfolgerung:Höhergradige akute Organtoxizität ist im untersuchten Kollektiv ein unabhängiger positiver prognostischer Faktor. Der Zusammenhang zwischen höhergradiger akuter Organtoxizität unter Radio(chemo)therapie und der Prognose sollte in prospektiven Studien weiter evaluiert werden.

Single-Dose Gamma-Irradiation Induces Up-Regulation of Chemokine Gene Expression and Recruitment of Granulocytes into the Portal Area but Not into Other Regions of Rat Hepatic Tissue

Liver damage is a serious clinical complication of gamma-irradiation. We therefore exposed rats to single-dose gamma-irradiation (25 Gy) that was focused on the liver. Three to six hours after irradiation, an increased number of neutrophils (but not mononuclear phagocytes) was observed by immunohistochemistry to be attached to portal vessels between and around the portal (myo)fibroblasts (smooth muscle actin and Thy-1(+) cells). MCP-1/CCL2 staining was also detected in the portal vessel walls, including some cells of the portal area. CC-chemokine (MCP-1/CCL2 and MCP-3/CCL7) and CXC-chemokine (KC/CXCL1, MIP-2/CXCL2, and LIX/CXCL5) gene expression was significantly induced in total RNA from irradiated livers. In laser capture microdissected samples, an early (1 to 3 hours) up-regulation of CCL2, CXCL1, CXCL8, and CXCR2 gene expression was detected in the portal area but not in the parenchyma; with the exception of CXCL1 gene expression. In addition, treatment with an antibody against MCP-1/CCL2 before irradiation led to an increase in gene expression of interferon-gamma and IP-10/CXCL10 in liver tissue without influencing the recruitment of granulocytes. Indeed, the CCL2, CXCL1, CXCL2, and CXCL5 genes were strongly expressed and further up-regulated in liver (myo)fibroblasts after irradiation (8 Gy). Taken together, these results suggest that gamma-irradiation of the liver induces a transient accumulation of granulocytes within the portal area and that (myo)fibroblasts of the portal vessels may be one of the major sources of the chemokines involved in neutrophil recruitment. Moreover, inhibition of more than one chemokine (eg, CXCL1 and CXCL8) may be necessary to reduce leukocytes recruitment.

PALB2 mutations in German and Russian patients with bilateral breast cancer.

Since germline mutations in the PALB2 (Partner and Localizer of BRCA2) gene have been identified as breast cancer (BC) susceptibility alleles, the geographical spread and risks associated with PALB2 mutations are subject of intense investigation. Patients with bilateral breast cancer constitute a valuable group for genetic studies. We have thus scanned the whole coding region of PALB2 in a total of 203 German or Russian bilateral breast cancer patients using an approach based on high-resolution melting analysis and direct sequencing of genomic DNA samples. Truncating PALB2 mutations were identified in 4/203 (2%) breast cancer patients with bilateral disease. The two nonsense mutations, p.E545X and p.Q921X, have not been previously described whereas the two other mutations, p.R414X and c.509_510delGA, are recurrent. Our results indicate that PALB2 germline mutations account for a small, but not negligible, proportion of bilateral breast carcinomas in German and Russian populations.

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.

Irradiation with protons for the individualized treatment of patients with locally advanced rectal cancer: A planning study with clinical implications

BACKGROUND AND PURPOSE Ongoing clinical trials aim to improve local control and overall survival rates by intensification of therapy regimen for patients with locally advanced rectal cancer. It is well known that whenever treatment is intensified, risk of therapy-related toxicity rises. An irradiation with protons could possibly present an approach to solve this dilemma by lowering the exposure to the organs-at-risk (OAR) without compromising tumor response. MATERIAL AND METHODS Twenty five consecutive patients were treated from 04/2009 to 5/2010. For all patients, four different treatment plans including protons, RapidArc, IMRT and 3D-conformal-technique were retrospectively calculated and analyzed according to dosimetric aspects. RESULTS Detailed DVH-analyses revealed that protons clearly reduced the dose to the OAR and entire normal tissue when compared to other techniques. Furthermore, the conformity index was significantly better and target volumes were covered consistent with the ICRU guidelines. CONCLUSIONS Planning results suggest that treatment with protons can improve the therapeutic tolerance for the irradiation of rectal cancer, particularly for patients scheduled for an irradiation with an intensified chemotherapy regimen and identified to be at high risk for acute therapy-related toxicity. However, clinical experiences and long-term observation are needed to assess tumor response and related toxicity rates.

Single fraction radiosurgery using Rapid Arc for treatment of intracranial targets

BackgroundStereotactic-Radio-Surgery (SRS) using Conformal-Arc-Therapy (CAT) is a well established irradiation technique for treatment of intracranial targets. Although small safety margins are required because of very high accuracy of patient positioning and exact online localisation, there are still disadvantages like long treatment time, high number of monitor units (MU) and covering of noncircular targets. This planning study analysed whether Rapid Arc (RA) with stereotactic localisation for single-fraction SRS can solve these problems.MethodsTen consecutive patients were treated with Linac-based SRS. Eight patients had one or more brain metastases. The other patients presented a symptomatic vestibularis schwannoma and an atypic meningeoma. For all patients, two plans (CAT/RA) were calculated and analysed.ResultsConformity was higher for RA with additional larger low-dose areas. Furthermore, RA reduced the number of MU and the treatment time for all patients. Dose to organs at risk were equal or slightly higher using RA in comparison to CAT.ConclusionsRA provides a new alternative for single-fraction SRS irradiation combining advantages of short treatment time with lower number of MU and better conformity in addition to accuracy of stereotactic localisation in selected cases with uncomplicated clinical realization.