Hans-Hermann Dubben

Tumor volume: a basic and specific response predictor in radiotherapy.

BACKGROUND AND PURPOSE Predictive assays of the response of tumor and normal tissues in individual patients offer the possibility of individualized prognosis and treatment decisions. For this purpose a variety of assays are currently being explored. The impact of tumor volume on radiotherapy outcome has long been recognized and in this paper its predictive potential is investigated. METHODS Re-evaluation of clinical data from the literature. RESULTS Tumor volume significantly influences radiotherapy outcome and in many sites it is likely a superior prognostic indicator to tumor stage, which reflects tumor size only partially and is mainly correlated to operability. Tumors even of identical stage may vary by factors of more than 100 in volume and neglect of this heterogeneity clearly reduces the power of a study considerably. The precision requirements for the measurement of tumor volume are small; +/-50% is sufficient for reasonable results. CONCLUSION The data evaluated here suggest that tumor volume is the most precise and most relevant predictor of radiotherapy outcome. Its determination is achievable with sufficient accuracy in most radiotherapy departments. Individual tumor volume should always be reported in clinical studies and considered in data analyses.

Systematic review of publication bias in studies on publication bias

Publication bias is a well known phenomenon in clinical literature,1 2 in which positive results have a better chance of being published, are published earlier, and are published in journals with higher impact factors. Conclusions exclusively based on published studies, therefore, can be misleading.3 Selective underreporting of research might be more widespread and more likely to have adverse consequences for patients than publication of deliberately falsified data.1 We investigated whether there is preferential publication of positive papers on publication bias. We identified studies that assessed the impact of publication bias in Medline (January 1993 to October 2003) using the search terms “publication bias”, “citation bias”, “language bias”, location bias”, “reference bias”, or “multiple publication bias”. We also searched the references of …

Potential pitfalls in the use of p-values and in interpretation of significance levels

In multiparameter analysis of clinical data the likelihood of obtaining significant results, just by chance, increases considerably with the overall number of tests performed. This can be compensated for by adjusting the p-values. Two tables are given from which adjusted p-values may be read off, providing a simple procedure to test the reliability of the results from clinical studies. Multivariate analyses often impress with extremely low p-values, but frequently these results turn out to be non-significant when the influence of multiple testing is considered. As a consequence the actually relevant results might be overlooked, because of the large number of spurious results accumulating in the literature. The use of inappropriate statistics hampers progress in clinical research. It is concluded that more care in the use of p-values in analysis and interpretation of clinical data is required.

Hyperfractionation: where do we stand?

Hyperfractionation is generally expected to allow an escalation of total dose, thereby increasing tumour control rate, without increasing the risk of late complications. The purpose of this review is to assess the empirical evidence for this therapeutic gain from hyperfractionated radiotherapy. Although extensive clinical data have been accumulated until now, especially on treatment of head and neck cancer, the line of evidence is not consistent. The present analysis indicates that the dose per fraction generally used in standard radiotherapy is already a good choice.

Local control, TCD50 and dose-time prescription habits in radiotherapy of head and neck tumours

Abstract Clinical data on head and neck tumours presented by Withers et al. (The hazard of accelerated tumour clonogen repopulation during radiotherapy. Acta Oncol. 27: 131–146, 1988) are reexamined. Recently it was argued that the relationship between TCD 50 and treatment time might be influenced by the practice of prescription [3,4]. This paper investigates the role of local tumour control rate in the interpretation of the data. In the genuine data set local tumour control rates were replaced by either tumour failure rate or by random numbers. TCD 50 values were calculated from the original and these manipulated data and related to treatment duration. TCD 50 increases with about 0.48 Gy/day in all cases. This unexpected result is explained by the lack of a dose-response relationship which causes a highly significant correlation between TCD 50 and prescribed dose. Consistently, multiple regression analysis reveals a significant impact of prescribed dose ( p 50 but not of treatment duration ( p > 0.05). The increase of TCD 50 with treatment time reflects solely dose-time prescription habits. The data provide no significant evidence either for an impact of treatment duration or for repopulation during radiotherapy in head and neck tumours. From this lack of evidence it may not be concluded that treatment duration is an unimportant parameter in radiotherapy.

Stellenwert der Strahlentherapie bei der Behandlung des meningealen Melanozytoms

Hintergrund: Das meningeale Melanozytom wird als seltene benigne Tumorentität mit hoher Rezidivneigung beschrieben. In der Literatur gibt es bislang keine fundierten Therapieempfehlungen, es liegen lediglich Fallberichte vor. Patienten und Methoden: 1997 wurde eine Patientin aufgrund eines Rezidivs, 1999 aufgrund zerebraler Metastasen eines spinalen meningealen Melanozytoms in unserer Abteilung bestrahlt. Dieser Fall gab Anlass zu einer Literaturrecherche im Hinblick auf mögliche Therapieoptionen. Alle seit Einführung des Begriffs meningeales Melanozytom (1972) publizierten und ausreichend dokumentierten Fälle wurden analysiert. Anhand publizierter und durch persönlichen Kontakt mit den Autoren gewonnener Daten wurden Rezidiv- und Gesamtüberlebensraten bis 5 Jahre nach Operation für die Therapiemodalitäten komplette Tumorresektion, inkomplette Resektion plus postoperative Strahlentherapie und alleinige inkomplette Resektion ermittelt. Die statistische Auswertung erfolgte mittels 2-Test sowie Kaplan-Meier-Analyse. Ergebnisse: 53 Patienten (inklusive der eigenen Patienten) erfüllten die Selektionskriterien. Nach kompletter Resektion ergaben sich verlichen mit der alleinigen inkompletten Resektion niedrigere Rezidiv- (4–38% versus 50–92%) und höhere Gesamtüberlebensraten (86–95% versus 30–58%). Nach inkompletter Resektion scheint eine postoperative Strahlentherapie die Prognose verbessern zu können (Rezidivraten 15–45%; Gesamtüberlebensraten 91–92%). Zwischen den Therapiemodalitäten komplette Resektion und inkomplette Resektion plus Strahlentherapie waren keine signifikanten Unterschiede erkennbar. Schlussfolgerungen: Bei der Behandlung des meningealen Melanozytoms muss von den drei verglichenen Therapiemodalitäten die komplette Tumorresektion als beste Option angesehen werden. Nach inkompletter Resektion ist eine postoperative Strahlentherapie in Erwägung zu ziehen. Ein bestimmtes Strahlentherapieregime kann derzeit nicht empfohlen werden, allerdings ist bei Vorliegen multipler kranialer oder spinaler Herde ene Bestrahlung des Neurokraniums oder der kraniospinalen Achse indiziert.Background: Meningeal melanocytoma is described as rare benign lesion with a high risk of recurrence. There are no well-substantiated treatment recommendations in the literature. Only case reports have been published by now. Patients and Methods: In 1997 a patient was irradiated for a recurrent spinal meningeal melanocytoma and 2 years later for brain metastases indicating malignant transformation. This case gave rise to a literature review for therapeutic options. All sufficiently documented cases published since 1972, when the term meningeal melanocytoma was established, were evaluated. Based on published and on original data recurrence and overall survival rates up to 5 years were calculated for three different therapeutic approaches, namely complete tumor resection, incomplete resection with subsequent radiotherapy, and incomplete resection alone. Statistical evaluation was performed using the 2test and Kaplan-Meier-analysis. Results: 53 patients (including our patient) met selection criteria. Complete tumor resection was superior to incomplete resection alone with lower recurrence (4–38% versus 50–92%) and better overall survival rates (86–95% vesus 30–58%). After incomplete resection radiotherapy seemed to improve prognosis (recurrence 15–45%; overall survival 91–92%). Between complete resection and incomplete resection plus radiotherapy no significant differences were observed. Conclusions: For meningeal melanocytoma complete resection must be regarded as the best of the modalities compared. After incomplete resection radiotherapy should be considered, although a specific radiotherapeutic regimen cannot be recommended at present. However, for multiple cranial or spinal lesions total cranial irradiation or craniospinal irradiation is indicated.

Influence of the Timing of a Concomitant Boost During Fractionated Irradiation of Rat Rhabdomyosarcoma R1H

Rhabdomyosarcomas R1H of the rat (WAG/Rij) were treated using fractionation schedules including a boost. The total dose was 60 Gy. Overall treatment time was 6 weeks. Four different boost schedules were applied: a single dose boost (12.15 Gy) at the last day of treatment, a single dose boost (12.15 Gy) at the first day of treatment, a schedule including the boost in 7 fractions during the first week, and a schedule including the boost in 10 fractions during the first week of treatment. A standard schedule with 30 fractions of 2 Gy without a boost was used for comparison. Initially accelerated schedules, i.e. those with a boost at start of treatment, revealed higher effect on tumour parenchyma as monitored by local control rate and net growth delay. This could be due to a decrease of radio-sensitivity, that is, an increase of the hypoxic fraction of clonogenic tumour cells during fractionated irradiation.

No effect of the hemoglobin solution HBOC-201 on the response of the rat R1H tumor to fractionated irradiation.

Background and Purpose:Tumor hypoxia is regarded as one important underlying feature of radioresistance. The authors report on an experimental approach to improve tumor response to radiation by combining fractionated irradiation with HBOC-201, an ultrapurified polymerized hemoglobin solution, which is currently used in clinical phase II/III trials as alternative oxygen carrier and proved to be highly effective in tissue oxygenation (tpO2).Material and Methods:: Subcutaneously growing rhabdomyosarcoma R1H tumors of the rat were treated with either 40 Gy (2 Gy/fraction, 20 fractions in 2 weeks, ambient) followed by graded top-up doses (clamped) alone, or in combination with HBOC-201, or with HBOC-201 plus carbogen (95% O2 + 5% CO2). Local tumor control (TCD50%) and growth delay were used as endpoints. In addition, the effect of HBOC-201 alone or in combination with carbogen on the tpO2 of tumor and muscle was determined using a flexible stationary probe (Licox, GMS).Results:TCD50% values of 119 Gy (95% confidence interval 103;135), 111 Gy (84;138), and 102 Gy (83;120) were determined for tumors irradiated alone, in combination with HBOC-201, and with HBOC-201 plus carbogen, respectively. Although the dose-response curves showed a slight shift to lower doses when HBOC-201 or HBOC-201 plus carbogen was added, the differences in TCD50% were not statistically significant. No effect was seen on the growth delay of recurrent tumors. HBOC-201 alone did not effect tumor or muscle tpO2. In combination with carbogen the mean tpO2 of muscle raised from 23.9 mmHg to 59.3 mmHg (p < 0.05), but this effect was less pronounced than the increase in tpO2 by carbogen alone.Conclusion:Low-dose application of HBOC-201 does not improve the response of the rhabdomyosarcoma R1H of the rat to fractionated irradiation.Hintergrund und Ziel:Strategien zur Überwindung der hypoxievermittelten Radioresistenz von Tumoren sind gegenwärtig von großem klinischen und wissenschaftlichen Interesse. Eine Verbesserung der Sauerstoffverfügbarkeit im Tumor kann als Folge der gesteigerten O2-Transportkapazität durch eine Erhöhung der Hämoglobinkonzentration erreicht werden. Die zellfreie Hämoglobinlösung HBOC-201 wird erfolgreich in klinischen Phase-II/III-Studien eingesetzt und vermag die Sauerstoffversorgung von Gewebe effektiv zu erhöhen. Die vorliegende Arbeit sollte klären, ob HBOC-201 im Rahmen einer fraktionierten Strahlentherapie die Tumorhypoxie verringern und das Therapieergebnis verbessern kann.Material und Methodik:Eine fraktionierte Bestrahlung von subkutan wachsenden R1H-Tumoren der Ratte wurde mit täglicher, niedrigdosierter i. v. Gabe von HBOC-201 bzw. von HBOC-201 plus Carbogen (95% O2 + 5% CO2) kombiniert. Es wurden Gesamtdosen von 40 Gy fraktioniert verabreicht (2 Gy/Fraktion, 20 Fraktionen in 2 Wochen) und mit Top-up-Dosen auf Gesamtdosen aufgesättigt, die eine Bestimmung der lokalen Tumorkontrolle ermöglichten. Neben der lokalen Kontrolldosis (TCD50%) wurde die Wachstumsverzögerung der Rezidive bestimmt. Zusätzlich wurde der Effekt von HBOC-201 allein und in Kombination mit Carbogen auf die Gewebsoxygenierung (tpO2) polarometrisch bestimmt.Ergebnisse:Die Kombination einer fraktionierten Bestrahlung mit HBOC-201 bzw. mit HBOC-201 plus Carbogen hatte keinen statistisch signifikanten Einfluss auf die lokale Tumorkontrolle. Es wurde eine nur geringfügige Verringerung der TCD50%-Werte von 119 Gy (95%-Konfidenzintervall: 103;135) auf 111 Gy (84;138) bzw. auf 102 Gy (83;120) beobachtet. Die Wachstumsverzögerung der Rezidive wies ebenfalls keine Veränderung auf. Die Oxygenierung von Tumor- und Muskelgewebe konnte durch Carbogenatmung, nicht aber durch HBOC-201 verbessert werden.Schlussfolgerung:Die Wirksamkeit einer fraktionierten Tumorbestrahlung wird durch niedrigdosierte Hämoglobinlösung HBOC-201 nicht verbessert.

Split-course radiotherapy: where do we stand?

Background: Split-course radiotherapy is only rarely applied in curative radiotherapy and there might be a number of arguments bo believe that continuous radiotherapy is superior to split-course treatment. In order to point out the evidence current treatment practice is based on, the available randomized trials and some prominent retrospective analyses on split-course radiotherapy were critically assessed. Material and Methods The analysis of the clinical results was based on published data only. Publications were searched in a Medline database. Results: Assessment of 13 randomized trials, including the data of 2,112 patients, revealed no significant difference between continuous-course and split-course radiotherapy. Astonishingly, the outcome of 77 radiotherapy studies on split-course, most of which are retrospective, seems to depend on the year of publication, suggesting publication bias. Conclusions: No clinically relevant difference between continuous and split-course radiotherapy could be found. This, of course, does not proof that there are indeed no differences but the data do not allow to draw clear-cut conclusions in favor of or against split-course radiotherapy due to methodological shortcomings of the studies.Hintergrund: Split-Course-Strahlentherapie wird bei kurativer Behandlung nur noch selten eingesetzt. Scheinbar gibt es viele Gründe, zu glauben, dass die Split-Course-Strahlentherapie einer kontinuierlichen Behandlung unterlegen ist. Um die Grundlage der gegenwärtigen Behandlungspraxis darzustellen, wurden randomisierte Studien und einige viel zitierte Arbeiten zum Thema Split-Course kritisch überprüft. Material und Methode: Die Analyse klinischer Ergebnisse beruht ausschließlich auf publizierten Daten. Die Publikationen wurden in der Medline-Datenbank gesucht. Ergebnis: Die Überprüfung von 13 randomisierten Studien mit insgesamt 2 112 Patienten zeigt keinen signifikanten Unterschied zwischen kontinuierlicher und Split-Course-Strahlentherapie. Erstaunlicherweise hängt das Ergebnis von 77 Split-Course-Strahlentherapiestudien, von denen die meisten retrospektiv waren, vom Erscheinungsjahr ab. Eine nahe liegende Erklärung dafür ist Publication Bias. Schlussfolgerung: Es wurde kein klinisch relevanter Unterschied zwischen kontinuierlicher und unterbrochener Strahlentherapie gefunden. Dies darf nicht als Beweis dafür gewertet werden, dass es tatsächlich keinen Unterschied gibt. Die gegenwärtige Datenlage, die auf methodischen Unzulänglichkeiten der bisher durchgeführten Studien beruht, erlaubt keine eindeutige Schlussfolgerung.

Proliferationsrate und Strahlenempfindlichkeit

In 1906 Bergonié and Tribondeau postulated a correlation between proliferation rate and radiosensitivity. Allowing for modern radiotherapeutic and radiobiological experience this postulate is no longer tenable.ZusammenfassungDas „Gesetz von Bergonié und Tribondeau” aus dem Jahre 1906 postuliert einen Zusammenhang zwischen Proliferationsrate und Strahlenempfindlichkeit. Vor dem Hintergrund moderner strahlentherapeutischer und strahlenbiologischer Erkenntnisse ist dieses Gesetz nicht mehr haltbar.AbstractIn 1906 Bergonié and Tribondeau postulated a correlation between proliferation rate and radiosensitivity. Allowing for modern radiotherapeutic and radiobiological experience this postulate is no longer tenable.