Dorothea Riesenbeck

Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer

BACKGROUND Preoperative chemotherapy improves survival in patients with stage III non-small-cell lung cancer (NSCLC) amenable to resection. We aimed to assess the additional effect of preoperative chemoradiation on tumour resection, pathological response, and survival in these patients. METHODS Between Oct 1, 1995, and July 1, 2003, patients with stage IIIA-IIIB NSCLC and invasive mediastinal assessment from 26 participating institutions of the German Lung Cancer Cooperative Group (GLCCG) were randomly assigned to one of two treatment groups. The intervention group were scheduled to receive three cycles of cisplatin and etoposide, followed by twice-daily radiation with concurrent carboplatin and vindesine, and then surgical resection (those with positive resection margins or unresectable disease were offered further twice-daily radiotherapy). The control group were scheduled to receive three cycles of cisplatin and etoposide, followed by surgery, and then further radiotherapy. The primary endpoint was median progression-free survival (PFS) in patients eligible for treatment after randomisation. Secondary endpoints in patients eligible for treatment after randomisation were overall survival (OS) and the proportion of patients undergoing surgery. Secondary endpoints in patients with tumour resection were the proportion with negative resection margins, the proportion with complete resection, the proportion with histopathological response, and the proportion with mediastinal downstaging. Additionally, exploratory (not prespecified) post-hoc analyses in terms of PFS and OS were done on patients not amenable to resection and on further subgroups of patients undergoing resection. Analyses were by intention to treat. This trial is registered on the ClinicalTrials.gov website, number NCT 00176137. FINDINGS 558 patients were randomly assigned. 34 patients did not meet inclusion criteria and were excluded. Of 524 eligible patients, 142 of 264 (54%) in the interventional group and 154 of 260 (59%) in the control group underwent surgery; 98 of 264 (37%) and 84 of 260 (32%) underwent complete resection. In patients with complete resection, the proportion of those with mediastinal downstaging (45 of 98 [46%] and 24 of 84 [29%], p=0.02) and pathological response (59 of 98 [60%] and 17 of 84 [20%], p<0.0001) favoured the interventional group. However, there was no difference in PFS (primary endpoint) between treatment groups-either in eligible patients (median PFS 9.5 months, range 1.0-117.0 [95% CI 8.3-11.2] vs 10.0 months, range 1.0-111.0 [8.9-11.5], 5-year PFS 16% [11-21] vs 14% [10-19], hazard ratio (HR) 0.99 [0.81-1.19], p=0.87), in those undergoing tumour resection, or in patients with complete resection. In both groups, 35% of patients undergoing surgery received a pneumonectomy (50/142 vs 54/154). In patients receiving a pneumonectomy, treatment-related mortality increased in the interventional group compared with the control group (7/50 [14%] vs 3/54 [6%]). INTERPRETATION In patients with stage III NSCLC amenable to surgery, preoperative chemoradiation in addition to chemotherapy increases pathological response and mediastinal downstaging, but does not improve survival. After induction with chemoradiation, pneumonectomy should be avoided. FUNDING German Cancer Aid (Bonn, Germany).

Evaluation of Different Biomarkers to Predict Individual Radiosensitivity in an Inter-Laboratory Comparison–Lessons for Future Studies

Radiotherapy is a powerful cure for several types of solid tumours, but its application is often limited because of severe side effects in individual patients. With the aim to find biomarkers capable of predicting normal tissue side reactions we analysed the radiation responses of cells from individual head and neck tumour and breast cancer patients of different clinical radiosensitivity in a multicentric study. Multiple parameters of cellular radiosensitivity were analysed in coded samples of peripheral blood lymphocytes (PBLs) and derived lymphoblastoid cell lines (LCLs) from 15 clinical radio-hypersensitive tumour patients and compared to age- and sex-matched non-radiosensitive patient controls and 15 lymphoblastoid cell lines from age- and sex- matched healthy controls of the KORA study. Experimental parameters included ionizing radiation (IR)-induced cell death (AnnexinV), induction and repair of DNA strand breaks (Comet assay), induction of yH2AX foci (as a result of DNA double strand breaks), and whole genome expression analyses. Considerable inter-individual differences in IR-induced DNA strand breaks and their repair and/or cell death could be detected in primary and immortalised cells with the applied assays. The group of clinically radiosensitive patients was not unequivocally distinguishable from normal responding patients nor were individual overreacting patients in the test system unambiguously identified by two different laboratories. Thus, the in vitro test systems investigated here seem not to be appropriate for a general prediction of clinical reactions during or after radiotherapy due to the experimental variability compared to the small effect of radiation sensitivity. Genome-wide expression analysis however revealed a set of 67 marker genes which were differentially induced 6 h after in vitro-irradiation in lymphocytes from radio-hypersensitive and non-radiosensitive patients. These results warrant future validation in larger cohorts in order to determine parameters potentially predictive for clinical radiosensitivity.

Ovarian Function Following Pelvic Irradiation in Prepubertal and Pubertal Girls and Young Adult Women

Purpose:To analyze the effect of pelvic radiotherapy on ovarian function in prepubertal and pubertal girls and young adult women.Patients and Methods:In a retrospective monoinstitutional analysis, patients < 30 years of age at diagnosis were included who had been irradiated between 1979 and 1998. The main tumor types were Hodgkin’s disease (38%), Ewing’s sarcoma (20%) and nephroblastoma (11%). Patients were classified into three groups according to the position of the ovary in relation to the radiation portals. Group 1 was defined by direct irradiation of both ovaries. Group 2 patients were included with both ovaries potentially located in the radiation portals. In group 3, at least one ovary was not directly irradiated. The median follow-up was 128 months.Results:16 of 55 analyzed patients were categorized in group 1. In ten of these patients, hormone status was evaluable. The ovarian doses were ≥ 15 Gy. Except for one patient treated with 15 Gy all developed hormone failure. Eight of 14 patients of group 2 were evaluable. Seven of these patients developed ovarian failure. 19 of 24 patients in group 3 were evaluable. Nine of these patients developed ovarian failure. The observed difference in the rate of ovarian failure between the groups is statistically significant (p = 0.045).Conclusion:All patients receiving > 15 Gy to the ovaries developed hormone failure. In one case of a patient receiving an ovarian dose of 15 Gy, hormone failure was not found. In case of pelvic irradiation excluding at least one ovary, approximately half of the patients developed ovarian dysfunction, probably also due to the effects of polychemotherapy.Ziel:Analyse des Einflusses einer Beckenbestrahlung auf die Ovarialfunktion bei Mädchen und jungen Frauen.Patienten und Methodik:In einer retrospektiven monoinstitutionalen Analyse wurden Patientinnen evaluiert, die in den Jahren 1979–1998 in der Klinik für Strahlentherapie des Universitätsklinikums Münster bestrahlt worden waren und bei Therapie < 30 Jahre waren. Die häufigsten Tumorentitäten waren Morbus Hodgkin (38%), Ewing-Sarkome (20%) and Nephroblastome (11%). Die Patientinnen wurden in drei Gruppen eingeteilt. Bei Patientinnen der Gruppe 1 wurden beide Ovarien bestrahlt. Bei Patientinnen der Gruppe 2 wurden beide Ovarien potentiell bestrahlt, und in Gruppe 3 wurde mindestens ein Ovar nicht bestrahlt. Die mediane Nachbeobachtungszeit beträgt 128 Monate.Ergebnisse:Von den analysierten Patientinnen wurden 16 in Gruppe 1 klassifiziert. Bei zehn dieser Patientinnen war der Hormonstatus evaluierbar. Die Ovarialdosis lag bei ≥ 15 Gy. Bis auf eine Patientin, die mit 15 Gy bestrahlt wurde, entwickelten alle weiteren Patientinnen eine Ovarialinsuffizienz. Von 14 Patientinnen der Gruppe 2 waren acht evaluierbar. Sieben davon wiesen eine Ovarialinsuffizienz auf. 19 von 24 Patientinnen in Gruppe 3 waren evaluierbar. Neun davon entwickelten eine Ovarialinsuffizienz. Der Unterschied zwischen den drei Gruppen in Bezug auf das Auftreten einer Insuffizienz ist signifikant (p = 0,045).Schlussfolgerung:Alle Patientinnen, die mit > 15 Gy an den Ovarien belastet wurden, entwickelten eine Hormoninsuffizienz. Eine Patientin mit 15 Gy Ovarialbelastung wies keine Ovarialinsuffizienz auf. Wenn mindestens ein Ovar nicht bestrahlt wurde, lag die Insuffizienzrate bei etwa 50%, wahrscheinlich mitbedingt durch die Chemotherapie.

Chronische Strahlenfolgen an den Zahnhartgeweben (“Strahlenkaries”) Klassifikation und Behandlungsansätze

Fragestellung: Die rasche Zahnhartgewebszerstörung nach einer Kopf-Hals-Bestrahlung wurde bereits vor fast 80 Jahren als “Strahlenkaries” beschrieben und ist seither als klinischer Befund in der Routine etabliert. Dennoch findet sich in der international vereinheitlichten Befundaufnahme und Dokumentation von Strahlenfolgen nach RTOG/EORTC bislang keine Klassifizierung dieser radiogenen Organveränderung. Material und Methode: Daten- und Bildmaterial von Strahlenfolgen an Zähnen von über 1 500 Patienten, die sich in periradiotherapeutischer Betreuung befanden, liegen der repräsentativen Auswahl zugrunde. Makroskopisch erkennbare Veränderungen, insbesondere das Ausmaß später Läsionen an den Zahnkronen, waren Grundlage einer Einteilung in vier Schweregrade. Leitlinie dieser Einteilung war die Systematik der Klassifizierungen von Strahlenfolgen nach RTOG/EORTC für andere Organe. Ergebnisse: Am gesamten Patientengut fanden sich inspektorisch keine frühen Strahlenfolgen an den Zähnen. In den ersten 90 Tagen nach Bestrahlungsbeginn gibt ungefähr ein Drittel der Patienten spontan reversible Hypersensitivitäten an, wahrscheinlich als Ausdruck einer temporären Hyperämie der Pulpa. Dagegen gelang die rangskalierte Bewertung von Merkmalausprägungen der Strahlenkaries als später Strahlenfolge in einer vergleichbaren Systematik zu den bereits etablierten RTOG/EORTC-Scores anderer Organe. Es wurden damit die Voraussetzungen geschaffen, die Strahlenkaries in die international vereinheitlichte RTOG/EORTC-Klassifizierung zu integrieren. Schlussfolgerungen: Die Dokumentation früher Strahlenfolgen an den Zahnhartgeweben ist derzeit vernachlässigbar. Dagegen haben die Befunderhebung und Dokumentation später Strahlenfolgen eine hohe Bedeutung. Die Identifikation einer Initialläsion an den Prädilektionsstellen “Zahnhals” und “Inzisalkante” führt zur rechtzeitigen Therapieeinleitung. Individuell ist damit eine wesentliche Voraussetzung für den Erhalt der Kaufunktion gegeben. Eine vereinheitlichte Dokumentation ist die unabdingbare Basis für die Beurteilung von Nebenwirkungen der radioonkologischen Therapie sowie der Wirksamkeit protektiver und supportiver Maßnahmen.Objectives: Since the first description of rapid destruction of dental hard tissues following head and neck radiotherapy 80 years ago, “radiation caries” is an established clinical finding. The internationally accepted clinical evaluation score RTOG/EORTC however is lacking a classification of this frequent radiogenic alteration. Material and Methods: Medical recores, data and images of radiation effects on the teeth of more than 1,500 patients, who underwent periradiotherapeutic care, were analyzed. Macroscopic alterations regarding the grade of late lesions of tooth crowns were used for a classification into 4 grades according to the RTOG/EORTC guidelines. Results: No early radiation effects were found by macroscopic inspection. In the first 90 days following radiotherapy 1/3 of the patients complained of reversible hypersensitivity, which may be related to a temporary hyperemia of the pulp. It was possible to classify radiation caries as a late radiation effect on a graded scale as known from RTOG/EORTC for other organ systems. This is a prerequisite for the integration of radiation caries into the international nomenclature of the RTOG/EORTC classification. Conclusions: The documentation of early radiation effects on dental hard tissues seems to be neglectable. On the other hand the documentation of late radiation effects has a high clinical impact. The identification of an initial lesion at the high-risk areas of the neck and incisal part of the tooth can be lead to a successful therapy as a major prerequisite for orofacial rehabilitation. An internationally standardized documentation is a basis for the evaluation of the side effects of radiooncotic therapy as well as the effectiveness of protective and supportive procedures.