Tobias Overbeck

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.

Population pharmacokinetics of melphalan and glutathione S-transferase polymorphisms in relation to side effects.

Melphalan is associated with severe side effects such as mucositis, diarrhea, and myelosuppression. We investigated how much the individual severity of these side effects is predicted by pharmacokinetics. In addition, we studied glutathione S‐transferase GSTM1, GSTT1, and GSTP1 polymorphisms in relation to adverse events. A high interindividual pharmacokinetic variability was observed in 84 patients. There was a linear correlation between creatinine and melphalan clearance (P=0.0004). Patients treated with a dose ⩾70 mg/m2 had a 23‐fold increased risk to develop mucositis (P<0.001) and a 12‐fold increased risk to develop diarrhea (P<0.001) compared with lower doses. The GSTP1 codon 105 polymorphism may be relevant for development of mucositis and the GSTT1 deletion may predict diarrhea, but these findings require confirmation. Melphalan‐induced side effects were significantly dependent only on dose. Therapeutic drug monitoring or genotyping for GST does not appear to be very helpful in optimizing therapy with melphalan.

Genetic polymorphisms in the amino acid transporters LAT1 and LAT2 in relation to the pharmacokinetics and side effects of melphalan.

Objectives Melphalan is widely used in the treatment of multiple myeloma. Pharmacokinetics of this alkylating drug shows high inter-individual variability. As melphalan is a phenylalanine derivative, the pharmacokinetic variability may be determined by genetic polymorphisms in the L-type amino acid transporters LAT1 (SLC7A5) and LAT2 (SLC7A8). Methods Pharmacokinetics were analysed in 64 patients after first administration of intravenous melphalan. Severity of side effects was documented according to WHO criteria. Genomic DNA was analysed for polymorphisms in LAT1 and LAT2 by sequencing of the entire coding region, intron-exon boundaries and 2 kb upstream promoter region. Selected polymorphisms in the common heavy chain of both transporters, the protein 4F2hc (SLC3A2), were analysed by single nucleotide primer extension. Results Melphalan pharmacokinetics was highly variable with up to 6.2-fold differences in total clearance. A total of 44 polymorphisms were identified in LAT1 and 21 polymorphisms in LAT2. From all variants, only five were in the coding region and only one heterozygous non-synonymous polymorphism (Ala94Thr) was found in LAT2. Numerous polymorphisms were found in the LAT1 and LAT2 5′-flanking regions but did not correlate with expression of the respective genes. No significant correlations could be observed between the polymorphisms in 4F2hc, LAT1, and LAT2 with melphalan pharmacokinetics or with melphalan side effects. Conclusions The study confirmed that these transporter genes are highly conserved, particularly in the coding sequences. Genetic variation in 4F2hc, LAT1, and LAT2 does not appear to be a major cause of inter-individual variability in pharmacokinetics and of adverse reactions to melphalan.

Two cases of psoriasis responding to erlotinib: time to revisiting inhibition of epidermal growth factor receptor in psoriasis therapy?.

Erlotinib inhibits the tyrosine kinase of epidermal growth factor receptor (EGFR) and is successfully used in lung cancer treatment. EGFR is essential in skin development and function and may have a role in the pathogenesis of psoriasis. Cutaneous side effects are very common in patients treated with erlotinib, and therapeutic use of erlotinib in dermatological disorders has therefore not been considered. We report two cases of patients with lung cancer and concomitant psoriasis treated with erlotinib with complete resolution of the skin problems. We present a review of the current literature on the topic.

Blastomatoid pulmonary carcinosarcoma: report of a case with a review of the literature

BackgroundPulmonary carcinosarcoma is a biphasic tumour with an unfavourable prognosis. The differential diagnosis includes pulmonary blastoma and is often challenging.Case presentationWe here describe a case of blastomatoid pulmonary carcinosarcoma in a 58-year-old patient, who underwent surgical resection. Histopathological examination revealed immature glandular epithelium resembling high-grade fetal adenocarcinoma expressing epithelial markers and membranous beta-catenin, and blastomatoid spindle cells with partial rhabdomyosarcoma-like differentiation. Both elements expressed p53, MDM2, and cyclin-dependent kinase 4 (CDK4), but not thyroid-transcription factor 1 (TTF-1). Mutation analysis of KRAS, EGFR, and beta-catenin revealed no mutations. Comparative genomic hybridization detected +1q, +6p, +6q24qter, +8q, +11q12q14, +11q23qter, +12q12q21, +12q24qter, +17q, +20q, -5q14q23, -9p13pter, -13q21q21, and amplifications at 12q14q21, 15q24qter, 20q11q12.ConclusionThe observed molecular and cytogenetic findings may provide additional tools for the differential diagnosis of biphasic pulmonary neoplasms. Furthermore, TP53, MDM2, CDK4, and PTPN1 may be involved in tumourigenesis.

Partial Response to First-Line Crizotinib in an Elderly Male Patient with ROS1 Translocation-Positive Lung Cancer.

We report on a 90-year-old male patient with a ROS1-translocated adenocarcinoma of the lung who was treated with crizotinib as first-line therapy. After 11 months of treatment, we noticed complete metabolic response as measured by 18F-FDG-PET/CT scan and a partial response according to RECIST criteria. This patient indicates that ROS1 translocations are not restricted to young age, female gender and low stage. Furthermore, this case illustrates exemplarily that crizotinib therapy is effective and manageable even as first-line treatment in elderly patients with comorbidities. Based on our findings, we recommend to include elderly patients with advanced pulmonary adenocarcinomas in molecular screening approaches for ROS1 translocations.

ABCA3 Phenotype in Non-Small Cell Lung Cancer Indicates Poor Outcome

Background: ATP-binding cassette transport protein A3 (ABCA3) is expressed in non-small cell lung cancer (NSCLC). We hypothesize that high-level ABCA3 expression may have a negative prognostic impact in patients with NSCLC. Methods: In 89 patients with NSCLC and curative intended surgery, we analyzed postoperative immunohistochemistry staining of primary tumors (anti-ABCA3) and clinicopathological parameters. We used a unidimensional four point score (FPS) system for intensity assessment and, furthermore, a combined bidimensional scoring of intensity and quantity resulting in the positive index (PI). Results: Former or never-smokers were more likely to have intermediate or strong ABCA3 unidimensional expression (FPS) compared with current smokers (p < 0.01). Patients >65 years of age had a higher probability of intermediate/strong ABCA3 expression (FPS) than younger patients (p < 0.05). In PI measurement, there were no significant correlations between ABCA3 and clinicopathological parameters. Patients with high-level PI had a significantly worse disease-free survival as well as overall survival than patients with low-level PI (p < 0.05). Conclusions: High-level PI of ABCA3 in NSCLC showed poor disease-free and overall survival in this patient cohort, potentially indicating the relevance of ABCA3 in lung cancer. This observation needs to be validated in larger series.

Partielles Ansprechen auf Crizotinib als Erstlinientherapie bei einem älteren männlichen Patienten mit ROS1-Translokations-positivem Bronchialkarzinom

Wir berichten hier über einen 90-jährigen männlichen Patienten mit ROS1-transloziertem Adenokarzinom der Lunge, der eine Erstlinientherapie mit Crizotinib erhielt. Nach 11-monatiger Behandlung waren ein vollständiges metabolisches Ansprechen laut 18F-FDG-PET/CT-Scan sowie ein partielles Ansprechen nach RECIST-Kriterien zu verzeichnen. Dieser Fall deutet darauf hin, dass ROS1-Translokationen sich nicht auf junges Alter, weibliches Geschlecht und niedrige Tumorstadien beschränken. Außerdem zeigt der Fall exemplarisch, dass die Crizotinib-Therapie auch als Erstlinientherapie bei älteren, komorbiden Patienten wirksam und beherrschbar sein kann. Auf Grundlage unserer Ergebnisse empfehlen wir, ältere Patienten mit fortgeschrittenem Adenokarzinom der Lunge in molekulare Screenings für ROS1-Translokationen einzuschließen.

Tumor Conference I

a Abteilung Hämatologie und Onkologie, Universitätsmedizin Göttingen, b Klinik und Poliklinik für Innere Medizin B, Universitätsmedizin Greifswald, c Klinik für Hämatologie und Onkologie, Pius-Hospital Oldenburg, d Ambulantes Aachener Zentrum für Lungenheilkunde, Luisenhospital Aachen, e Klinik und Poliklinik für Nuklearmedizin, Ludwig-Maximilians-Universität München, f Klinik für Thoraxchirurgie, Evangelische Lungenklinik Berlin, g Klinik und Poliklinik für Nuklearmedizin, Klinikum der Universität München – Campus Innenstadt, h Klinik für Strahlentherapie, Universitätsklinikum Essen, Deutschland