Bernhard Vanselow

Predictive Value of the Tumor Oxygenation by Means of pO2 Histography in Patients with Advanced Head and Neck Cancer

Purpose The purpose of this analysis was to evaluate the potential of the tumor oxygenation by means of Eppendorf pO2 histography as a predictive test to select patients for treatment alternatives. Patients and Methods: Pretreatment tumor pO2 histographies of locoregional lymph node metastases were assessed in 194 patients with squamous cell carcinoma of the head and neck. Included the analysis were 134 patients who received a primary radio- or radiochemotherapy with a radiation dose of ≥ 60 Gy, and who had no distant metastasis at beginning of the therapy. Results: The Cox regression analysis revealed the fraction of pO2 values ≤ 2.5 mm Hg (p = 0.004), age (p = 0,04) and radiotherapy/radiochemotherapy (p = 0.03) as significant independent prognostic factors for the survival. The positive and negative predictive values were calculated using different cut-off values of the fraction of pO2 values ≤ mm Hg and the survival status at 1 or 2 years after beginning of the therapy as endpoint. The highest positive and negative predictive values of all cut-off values were 0.50 and 0.41 at 1 year, and 0.81 and 0.26 at 2 years. Conclusions: Our data confirm the influence of the tumor oxygenation on the prognosis of patients with squamous cell carcinoma of the head and neck after radiotherapy. However, the calculated positive and negative predictive values suggest that the pO2 histography alone is not sufficient to be used as a predictive test to successfully select patients for treatment alternatives.Hintergrund Hintergrund dieser Arbeit war, die Wertigkeit der Tumoroxygenierung, gemessen mittels Eppendorf-Histographie, als prädiktiver Test zur Individualisierung der Therapie zu bestimmen. Patienten und Methoden: Bei 194 Patienten mit Plattenepithelkarzinomen des Kopf-Hals-Bereichs wurden prätherapeutische pO2-Histographien bei lokoregionären Lymphknotenmetastasen durchgeführt. In die statistische Analyse der Einflussfaktoren auf das Überleben wurden 134 Patienten aufgenommen, die eine primäre Radio- oder simultane Radiochemotherapie mit einer Mindestdosis von 60 Gy erhielten und bei denen keine Fernmetastasierung vor Therapie vorlag. Ergebnisse: Die Coxsche Regressionsanalyse ergab als signifikante unabhängige Einflussfaktoren auf das Überleben die Fraktion der pO2-Werte ≤ 2,5 mm Hg (p = 0,004), das Alter (p = 0,04) und die Therapiemodalität (Radiotherapie vs. Radiochemotherapie p = 0,03). Der positive und der negative prädiktive Wert wurden im Hinblick auf das Überleben nach 1 bzw. nach 2 Jahren für verschiedene Cut-off-Werte der Fraktion der pO2-Werte ≤ 2,5 mm Hg ermittelt. Der höchste positive oder negative prädiktive Wert aller Cut-off-Werte betrug hierbei 0,50 und 0,41 nach 1 Jahr bzw. 0,81 und 0,26 nach 2 Jahren. Schlussfolgerung: Unsere Daten bestätigen den Einfluss der Tumoroxygenierung auf die Prognose bei Patienten mit Plattenepithelkarzinomen des Kopf-Hals-Bereichs. Der prädiktive Wert der Tumoroxygenierung allein, gemessen mitels Eppendorf-Histographie, scheint aber nicht ausreichend zu sein, um Patienten erfolgreich für verschiedene Therapieoptionen selektionieren zu können.

Repeatability and prognostic impact of the pretreatment pO2 histography in patients with advanced head and neck cancer

PURPOSE The purpose of this study was to evaluate the repeatability and the predictive relevance of the pretreatment pO(2) histography on the survival of patients with advanced head and neck cancer. PATIENTS AND METHODS From July 1995 to August 1998, polarographic pO(2) measurements of lymph node metastases before therapy were performed in altogether 60 patients with histologically proven squamous cell carcinoma of the head and neck using the Eppendorf histograph. Forty-one of 60 patients were treated with an accelerated-hyperfractionated radiotherapy regimen with or without simultaneous chemotherapy as part of a multicenter phase III study. In 23 of 60 patients, two repeated independent measurements of the same tumor were performed with a time interval of approximately 24 h between the two measurements. RESULTS The multivariate analysis revealed the fraction of pO(2) values </=2.5 mmHg as the only significant prognostic factor for the survival (P=0.05) in the 41 study patients. No correlation was found between tumour oxygenation and the volume of the measured lymph node metastases or the haemoglobin concentration. The coefficient of variation of the repeated measurements representing the assay variability was 57-68% of the total variation. CONCLUSION Our data support the concept of the relevance of the pretreatment tumour hypoxia for the prognosis of patients with head and neck cancer after fractionated radiotherapy. Because of the relative poor repeatability of the pO(2) histography and the small patient number, further studies are required to confirm this finding and to evaluate the most relevant oxygenation parameter for clinical endpoints.

Oxygenation of advanced head and neck cancer: Prognostic marker for the response to primary radiochemotherapy

Recent clinical studies suggest that the degree of tumor oxygenation may be predictive of the response of radiation therapy for cancer. In an exploratory investigation of cervical lymph node metastases in 27 patients with advanced squamous cell carcinoma of the oropharynx and hypopharynx, this relationship was investigated by means of oxygen measurements with an Eppendorf PO (2) histograph. The measurements were made before the start of radiation therapy and after the first week of therapy. Clinical response was evaluated 6 weeks after the completion of therapy. Before therapy, marked hypoxia was observed in the lymph node metastases, with a mean PO (2) value of 16.1 +/- 8.2 mm Hg and a hypoxic fraction (PO (2) < 10 mm Hg) of 56.4% +/- 20.0%. After the first week of radiation (9 Gy) there was a general reoxygenation (DeltaPO (2) = 5.0 +/- 10.1 mm Hg, P < 0.05; Deltahypoxic fraction = -11.3% +/- 31.3%, P = 0.11). A relationship between the degree of reoxygenation and tumor response was not observed. Patients without at least partial lymph node response (n = 8) showed poorer pretherapeutic oxygenation (PO (2) mean = 11.1 +/- 2.9 mm Hg) than those who responded to the therapy (n = 19, PO (2) mean = 18.2 +/- 8.8 mm Hg). In this investigation of a defined set of patients with advanced carcinoma of the oropharynx and hypopharynx, we found that pretherapeutic oxygenation data are predictive for the therapeutic response to radiation therapy or radiochemotherapy.

Prognostischer Stellenwert des Hämoglobinwertes vor primärer Radiochemotherapie von Kopf-Hals-Karzinomen

ZusammenfassungDer prätherapeutische Hämoglobin-Wert (Hb) wird als einer der wichtigsten Einflussgrößen für den Erfolg einer Strahlentherapie diskutiert; wurde jedoch bislang im klinischen Kontext anderer Risikofaktoren bei fortgeschrittenen Kopf-Hals-Tumoren kaum systematisch untersucht.In den Jahren 1992–1997 wurden in Kooperation der Universitäts-HNO- und -Strahlenklinik Heidelberg 2 prospektive multizentrische Studien zur primären Radiochemotherapie bei nichtresektablen Stadium-III/IV-Kopf-Hals-Karzinomen durchgeführt, in deren Rahmen insgesamt 125 Patienten behandelt wurden (Studienleitung: Herr Prof. Dr. R.-P. Müller; Köln). Studie A (Phase II, 1992–1995) rekrutierte 62 und Studie B (Phase III, 1995–1997) 63 Patienten. Neben dem Ausgangs-Hb-Wert wurden weitere, als prognostisch wichtig eingestufte klinische Parameter wie die Tumoroxygenierung, das Gesamttumorvolumen (total tumor volume, TTV), TNM, Tumorlokalisation, Alter und “performance status” erfasst und bezüglich ihres prädiktiven Wertes überprüft (Nachbeobachtungszeit 43 Monate).In der Gesamtbetrachtung (125 Patienten) setzten sich der Hb-Wert und das TTV als die stärksten, von einander unabhängigen, prognostischen Parameter, bezogen auf die Endpunkte Überleben und lokoregionäre Kontrollzeit, durch (bivariate Analyse: HbMedian (98 ml): Hazard-Ratio: 2,0 [p=0,006]. Bei nur 3 Patienten wurde eine Anämie mit Hb-Werten unter 10 g/dl gesehen. Die Tumoroxygenierung zeigte lediglich eine signifikante Korrelation mit dem initialen Therapieansprechen, die sich in den klinischen Verläufen nicht widerspiegelte. Eine Korrelation zwischen Hb-Werten und Tumoroxygenierungsparametern konnte nicht gesehen werden.Die Ergebnisse der Studie unterstreichen die hohe klinische Bedeutung des Ausgangs-Hb-Wertes für den Erfolg nach primärer Radiochemotherapie von fortgeschrittenen Kopf-Hals-Tumoren und unterstützen die Forderung nach randomisierten Studien zur Prüfung der Wertigkeit der prätherapeutischen Hb-Substitution bzw. -Anhebung durch Erythropoietin.AbstractThe pretherapeutic hemoglobin level (Hb) has been postulated to constitute a prognostic marker for outcome after primary chemoradiation of patients with advanced cancer of the head and neck. However, this hypothesis has not been tested systematically in large study samples.In the years 1992–1997, 125 patients with advanced head and neck cancer (stages III/IV UICC) were treated with primarychemoradiation in two different prospective multicentric trials, 62 patients in trial A (phase II, 1992–1995), and 63 in trial B (phase III, 1995–1997). Beside initial Hb, other pretherapeutic parameters with potential prognostic relevance were assessed and correlated with clinical outcome after 43-months follow-up: total tumor volume (TTV; calculated in initial CT scans), tumor oxygenation (polarographic measurements with Eppendorf histography), TNM, tumor localization, age, and performance status.The evaluation of the clinical end points (progression-free and overall survival and local tumor control) revealed that Hb and TTV were independent parameters with strong predictive character of outcome after primary chemoradiation in both trials (n=125). Bivariate analysis showed < median (13.5 g/dl) a hazard ratio of 2.1 (P=0.002) for Hb; and > median (98 ml) a Hazard ratio of 2.0 (P=0.006) for TTV. Severe anemia (Hb<10 g/dl) was an adverse factor in three patients. Hypoxia was associated with poorer initial therapeutic response but was not predictive of clinical outcome. Furthermore, tumor oxygenation showed no correlation with Hb. The other parameters examined failed to show prognostic significance.Our results indicate a high prognostic value of initial Hb for outcome after primary chemoradiation in advanced head and neck cancer and imply a therapeutic benefit of Hb substitution or erythropoietin administration. We propose to test this in randomized clinical trials.

Prognostic impact of reoxygenation in advanced cancer of the head and neck during the initial course of chemoradiation or radiotherapy alone.

Previous studies have shown that radiation of hypoxic tumors can result in reoxygenation phenomenon. The relevance of this phenomenon for prognosis is unclear. This study analyzes whether the presence of hypoxia, or the extent to which reoxygenation occurs during the initial phase of primary chemoradiation or radiotherapy, can predict the clinical outcome in advanced tumors of the head and neck.

Rise of oxygenation in cervical lymph node metastasis during the initial course of radiochemotherapy

It has been hypothesized that during radiation treatment a reoxygenation of hypoxic tumor tissue takes place. To test this hypothesis, we have investigated whether reoxygenation in lymph node metastases could be determined by invasive Po2 measurements. Through a hypodermic needle inserted transcutaneously into tumor-Positive lymph nodes, Polarographic oxygen determinations were made in 18 patients with advanced squamous cell carcinomas of the oropharynx and hypopharynx. These measurements were performed before therapy and a week after the onset of radiotherapy or radiochemotherapy, respectively. Low Po2 values before treatment (mean value of the patients median was 12.6 mm Hg Po2) and a mean hypoxic fraction (Po2 < 5 mm Hg) of 39.6% indicated manifest tumor hypoxia. After 1 week of treatment, a significant increase in the median PO2 (mean value of shift: 7.3 mm Hg) and a reduction in the hypoxic fraction (mean value of shift: 13.4% Po2 < 5 mm Hg, P < 0.03) were observed after both radiotherapy and radiochemotherapy. Thus invasive PO2 histography fulfills the requirements for a method to confirm tumor hypoxia in head and neck tumors. The results obtained indicate that reoxygenation occurs during the initial phases of radiotherapy and radiochemotherapy, and they will form the basis for future comparative investigations on the Possible influence of hypoxic parameters on tumor responsiveness toward radiation and radiochemotherapy.