Thomas Hehr

A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck

BackgroundFormer meta-analyses have shown a survival benefit for the addition of chemotherapy (CHX) to radiotherapy (RT) and to some extent also for the use of hyperfractionated radiation therapy (HFRT) and accelerated radiation therapy (AFRT) in locally advanced squamous cell carcinoma (SCC) of the head and neck. However, the publication of new studies and the fact that many older studies that were included in these former meta-analyses used obsolete radiation doses, CHX schedules or study designs prompted us to carry out a new analysis using strict inclusion criteria.MethodsRandomised trials testing curatively intended RT (≥60 Gy in >4 weeks/>50 Gy in <4 weeks) on SCC of the oral cavity, oropharynx, hypopharynx, and larynx published as full paper or in abstract form between 1975 and 2003 were eligible. Trials comparing RT alone with concurrent or alternating chemoradiation (5-fluorouracil (5-FU), cisplatin, carboplatin, mitomycin C) were analyzed according to the employed radiation schedule and the used CHX regimen. Studies comparing conventionally fractionated radiotherapy (CFRT) with either HFRT or AFRT without CHX were separately examined. End point of the meta-analysis was overall survival.ResultsThirty-two trials with a total of 10 225 patients were included into the meta-analysis. An overall survival benefit of 12.0 months was observed for the addition of simultaneous CHX to either CFRT or HFRT/AFRT (p < 0.001). Separate analyses by cytostatic drug indicate a prolongation of survival of 24.0 months, 16.8 months, 6.7 months, and 4.0 months, respectively, for the simultaneous administration of 5-FU, cisplatin-based, carboplatin-based, and mitomycin C-based CHX to RT (each p < 0.01). Whereas no significant gain in overall survival was observed for AFRT in comparison to CFRT, a substantial prolongation of median survival (14.2 months, p < 0.001) was seen for HFRT compared to CFRT (both without CHX).ConclusionRT combined with simultaneous 5-FU, cisplatin, carboplatin, and mitomycin C as single drug or combinations of 5-FU with one of the other drugs results in a large survival advantage irrespective the employed radiation schedule. If radiation therapy is used as single modality, hyperfractionation leads to a significant improvement of overall survival. Accelerated radiation therapy alone, especially when given as split course radiation schedule or extremely accelerated treatments with decreased total dose, does not increase overall survival.

18F-FDG PET for assessment of therapy response and preoperative re-evaluation after neoadjuvant radio-chemotherapy in stage III non-small cell lung cancer

PurposeThe aim of this study was to evaluate FDG-PET for assessment of therapy response and for prediction of patient outcome after neo-adjuvant radio-chemotherapy (NARCT) of advanced non-small cell lung cancer (NSCLC).MethodsSeventy patients with histologically proven stage III NSCLC underwent FDG-PET investigations before and after NARCT. Changes in FDG uptake and PET findings after completion of NARCT were compared with (1) the histology of tumour samples obtained at surgery or repeat mediastinoscopy, and (2) treatment results in terms of achieved operability and long-term survival.ResultsThe mean average FDG uptake of the primary tumours in the patient group decreased significantly during NARCT (p = 0.004). Sensitivity, specificity and overall accuracy of FDG-PET were 94.5%, 80% and 91%, respectively, for the detection of residual viable primary tumour, and 77%, 68% and 73%, respectively, for the presence of lymph node metastases. A negative PET scan or a reduction in the standardised uptake value (SUV) of more than 80% was the best predictive factor for a favourable outcome of further treatment. Progressive disease according to PET (new tumour manifestations or increasing SUV) was significantly correlated with an unfavourable outcome (p = 0.005). In this subgroup, survival of patients who underwent surgery was not significantly different from survival among those who did not undergo surgery, whereas for the whole patient group, complete tumour resection had a significant influence on outcome.ConclusionFDG-PET is suitable to assess response to NARCT in patients with stage III NSCLC accurately. It was highly predictive for treatment outcome and patient survival. PET may be helpful in improving restaging after NARCT by allowing reliable assessment of residual tumour viability.

Oral diadochokinesis in neurological dysarthrias

Rapid syllable repetitions require alternating articulatory movements and, thus, provide a test for oral diadochokinesis. The present study performed an acoustic analysis of rapid syllable repetitions in patients suffering from idiopathic Parkinsons disease (n = 17), Huntingtons chorea (n = 14), Friedreichs ataxia (n = 9), or from a purely cerebellar syndrome (n = 13). Four parameters were considered: the mean number of syllables per train, the median syllable duration with its variation coefficient, and articulatory imprecision in terms of the percentage of incomplete closures. Apart from a few subjects with minor motor deficits only, in all patients at least one of the four measures of diadochokinesis exceeded the normal range. Accordingly, discriminant analysis revealed a highly significant difference between controls and patients with respect to the considered parameters. Thus, oral diadochokinesis tasks represent a sensitive measure of orofacial motor impairment. Moreover, multivariate analysis showed that Parkinsons disease and Friedreichs ataxia are characterized by a highly specific profile of diadochokinesis performance.

Is standardised 18F-FDG uptake value an outcome predictor in patients with stage III non-small cell lung cancer?

PurposeRecent studies have demonstrated the relevance of 18F-FDG uptake as an independent prognostic factor for recurrence of operable non-small cell lung cancer (NSCLC). This corresponds with the experimental finding that FDG uptake correlates with the proliferative activity of tumour cells (Higashi et al., J Nucl Med 2000;41:85-92). On the basis of these observations, we studied the influence of FDG uptake on prognosis and occurrence of distant metastases in patients with advanced NSCLC.MethodsOne hundred and fifty-nine patients with NSCLC of UICC stage IIIA or IIIB were included in the study. In all patients, neoadjuvant treatment was planned to achieve operability. FDG PET was performed as an additional staging procedure prior to the initiation of therapy. Clinical outcome data in terms of overall survival, disease-free survival and incidence of distant metastases could be obtained for 137 patients and were correlated with the average standardised uptake value of the tumour (SUVavg). Furthermore, other factors influencing SUVavg and patient outcome (histological tumour type, grading, UICC stage, tumour size) were analysed.ResultsSUVavg was significantly influenced by tumour histology, UICC stage and tumour size. No significant difference could be shown for grading. In 38 out of the 159 patients (24%), FDG PET revealed previously unsuspected distant metastases. The incidence of distant metastases significantly correlated with SUVavg. Overall survival tended to decrease with increasing SUVavg; however, significance was only reached when a cut-off of 12.0 was applied (p=0.05).ConclusionFDG uptake is an independent prognostic factor in patients with UICC stage III NSCLC, although less distinctively so than has been reported for stage I/II tumours.

Phase II Trial of a Trimodality Regimen for Stage III Non-Small-Cell Lung Cancer Using Chemotherapy As Induction Treatment With Concurrent Hyperfractionated Chemoradiation With Carboplatin and Paclitaxel Followed by Subsequent Resection: A Single-Center Study

PURPOSE We started a phase II trial of induction chemotherapy and concurrent hyperfractionated chemoradiotherapy followed by either surgery or boost chemoradiotherapy in patients with advanced, stage III disease. The purpose is to achieve better survival in the surgery group with minimum morbidity and mortality. PATIENTS AND METHODS Patients treated from 1998 to 2002 with neoadjuvant chemoradiotherapy and surgical resection for stage III NSCLC were analyzed. The treatment consisted of four cycles of induction chemotherapy with carboplatin/paclitaxel followed by chemoradiotherapy with a reduced dose of carboplatin/paclitaxel and accelerated hyperfractionated radiotherapy with 1.5 Gy twice daily up to 45 Gy. After restaging, operable patients underwent thoracotomy. Inoperable patients received chemoradiotherapy up to 63 Gy. Study end points included resectability, pathologic response, and survival. Results One hundred twenty patients were enrolled; 25% patients had stage IIIA, 73% had stage IIIB, and 2% stage IV. After treatment, 47.5% had downstaging, 29.2% had stable disease, and 23.3% had progressive disease. Thirty patients (25%) were not eligible for operation because of progressive disease, stable disease, and/or functional deterioration with one treatment-related death. The 30-day mortality was 5% in patients who underwent operation. The 5-year survival rate for 120 patients was 21.7%, and it was 43.1% in patients with complete resection. In postoperative patients with stage N0 disease, 5-year survival was 53.3%; if stage N2 or N3 disease was still present, 5-year survival was 33.3%. CONCLUSION Staging and treatment with chemoradiotherapy and complete resection performed in experienced centers achieve acceptable morbidity and mortality.

Positron Emission Tomography/Computed Tomography and Whole-Body Magnetic Resonance Imaging in Staging of Advanced Nonsmall Cell Lung Cancer-Initial Results

Objective:To evaluate and compare positron emission tomography/computed tomography (PET/CT) with whole-body magnetic resonance imaging (wbMRI) in the correct staging of patients with advanced nonsmall cell lung cancer (NSCLC). Materials and Methods:Fifty-two patients with an NSCLC stage IIIa or IIIb (36 males and 16 females) were included in this study. Patients were referred to our department for restaging. Within 1 week PET/CT and wbMRI were performed in all patients. Images were examined independently by 2 experienced physicians from the Department of Nuclear Medicine and Radiology. Afterward, consensus reading was performed. In 22 patients, surgery served as gold standard, whereas in 30 patients, follow-up controls (after 2 months) were performed. Results:The use of wbMRI correctly T-staged all patients. Especially volume interpolated breathhold examination sequence correctly T-staged all tumors. PET/CT did not correctly stage chest wall infiltration in 4 cases [sensitivity 92.3% (P < 0.05 to wbMRI)/specificity 100%], verified by surgery. PET/CT correctly N-staged 51 patients (sensitivity 96.1%/specificity 100%). WbMRI showed a significant tendency to understage N-status [sensitivity 88.5% (P < 0.05)/specificity 96.1%]. Different N-status by PET/CT changed operability in 4 patients. In 2 patients, distant metastases were detected by both techniques. Conclusion:In the correct staging of advanced NSCLC, PET/CT has advantages in N-staging. This is of high relevance for therapy planning. WbMRI especially using volume interpolated breathhold examination sequences, has certain advantages in T-staging.

Impact of staging with 18F-FDG-PET on outcome of patients with stage III non-small cell lung cancer: PET identifies potential survivors

Abstract:Purpose:The aim of this study was to analyse the impact of FDG-PET staging on treatment results of neo-adjuvant radiochemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We compared prospectively the outcome of two patient groups with stage III NSCLC undergoing the same neo-adjuvant radio-chemotherapy (NARCT). In one group, FDG-PET was part of the pretherapeutic staging, whereas in the other group, no PET scans were performed.Methods:One hundred and eighty-eight patients with advanced stage III NSCLC were selected for a phase II trial of NARCT. The first 115 patients underwent conventional workup (CWU) and FDG-PET before inclusion (group I); the remaining 73 patients underwent CWU only (group II). All patients were followed up according to a standardised protocol for at least 11 months (up to 64 months). Overall survival and disease-free survival were used as parameters of therapeutic success and analysed statistically.Results:After staging, 157/188 patients were included in the clinical trial. Thirty-one were excluded owing to the results of FDG-PET, in most cases because of the detection of previously unknown distant metastases. Overall survival and metastasis-free survival were significantly longer in patients of group I stratified by FDG-PET than in group II (p=0.006 and 0.02 respectively). Another significant factor for survival was complete tumour resection (p=0.02). Gender, histological tumour type, tumour grade and UICC stage had no significant influence.Conclusion:Pretherapeutic staging by FDG-PET significantly influences the results of NARCT and subsequent surgery by identifying patients not eligible for curative treatment.

First Experiences of Radiation Treatment Planning with PET/CT

Background:Positron emission tomography/computed tomography (PET/CT) is composed of modern CT and PET technology in one machine enabling examinations of patients in one session in the same position. Its value for modern radiation treatment planning is under investigation.Methods:In 53 patients with head-and-neck (n = 11), non-small cell lung (n = 16), prostate (n = 14) and other cancers (n = 12), a PET/CT investigation was performed. During the diagnostic examination process an integrated scan under radiation treatment-planning conditions was included. Interpretation and delineation of macroscopic tumor were done in an interdisciplinary approach. Treatment changes occurred after critical interpretation of the PET/CT findings by the responsible radiotherapist. Analysis is descriptive with regard to changes in treatment intention, mode, radiation volumes and doses.Results:Examinations were well tolerated. CT datasets in treatment position could be used for planning. Delineation of macroscopic tumor led to changes of the planning target volume after PET/CT 15 times, total dose was modified twelve times. PET/CT examinations led to changes of the general treatment mode in 19 cases. Using the separate CT and PET datasets, fusion in the planning software was easily performed in all patients due to the use of the same positioning and immobilization devices in PET/CT.Conclusion:Despite the low number of patients and an expectable bias of selection, the first results are encouraging to perform more extended and detailed trials of this technology in radiotherapy planning. Whether PET/CT is superior to PET alone is part of ongoing investigations.Hintergrund:Die Positronenemissionstomographie/Computertomographie (PET/CT) ist eine Weiterentwicklung der Einzelkomponenten moderner CT- und PET-Technologie in einer kombinierten Hybridmaschine, die eine Untersuchung in einer Sitzung in derselben Position ermöglicht. Die Bedeutung für die moderne Strahlentherapie wird intensiv erforscht.Methodik:Bei 53 Patienten mit fortgeschrittenen Kopf-Hals- (n = 11), nichtkleinzelligen Bronchial- (n = 16) und Prostatakarzinomen (n = 14) sowie anderen Tumoren (n = 12) wurde eine PET/CT durchgeführt. Während der diagnostischen Untersuchung wurden die Patienten in Bestrahlungsposition gelagert und ein Scan zur Bestrahlungsplanung integriert. Die Interpretation und Einzeichnung makroskopischen Tumors wurden in einem interdisziplinären Ansatz aus erfahrenem Strahlentherapeut, Nuklearmediziner und radiologischem Diagnostiker vollzogen. Änderungen der Behandlung wurden eingeleitet, wenn sich nach kritischer klinischer Abschätzung der PET/CT-Ergebnisse relevante neue Befunde ergaben. Die Analyse ist deskriptiv in Bezug auf Änderungen von Behandlungsmodalität, -intention, Bestrahlungsvolumen und -dosis.Ergebnisse:Die Untersuchungen mit der PET/CT wurden von den Patienten gut toleriert. Die CT-Datensätze in Behandlungsposition konnten für die Planung verwendet werden. Die Einzeichnung des makroskopischen Tumors führte nach 15 Untersuchungen (26%) zu Änderungen des Planungszielvolumens. Die Gesamtdosis wurde nach zwölf PET/CT-Untersuchungen (21%) modifiziert. PET/CT führte 19-mal (33%) zu Änderungen des generellen Behandlungsmodus. Die separaten CT- und PET-Datensätze der Patienten in derselben Position mit denselben Immobilisierungshilfen konnten zur Fusion in der Planungssoftware einfach genutzt werden.Schlussfolgerung:Trotz der relativ niedrigen Patientenzahl und eines möglichen Selektionsfehlers sind die ersten Ergebnisse erfolgversprechend, um weitere, ausgedehntere Untersuchungen mit großen Patientenzahlen durchzuführen. Inwieweit die kombinierte PET/CT den Einzelkomponenten mit späterer Fusion überlegen ist, sollte in diesem Zusammenhang evaluiert werden.

Re-surgery and chest wall re-irradiation for recurrent breast cancer - a second curative approach

BackgroundRepeat radiation is a rarely used treatment strategy that must be performed with caution. The efficacy and toxicity of a second curative radiotherapy series was investigated in cases of recurrent breast cancer.MethodsForty-two patients treated from 1993 to 2003 with resection (n = 30) and postoperative re-irradiation or definitive re-irradiation (n = 12) for recurrent breast cancer were enrolled in the study. Concurrent hyperthermia was performed in 29 patients. The median age was 57 years. The median pre-radiation exposure was 54Gy. Re-irradiation was conventionally fractionated to a median total dose of 60Gy.ResultsAfter a median follow-up of 41 months (range 3-92 months) higher graded late toxicity > G3 according to CTC 3.0 and LENT-SOMA was not observed. The estimated 5-year local control rate reached 62%. The estimated 5-year overall survival rate was 59%. Significantly inferior survival was associated with recurrence within two years (40 vs. 71%, p < ([0-9]).01) and presence of macroscopic tumour load (24 vs. 75%, p = 0.03).ConclusionsRepeat radiotherapy for recurrent breast cancer with total radiation doses of 60 Gy and the addition of hyperthermia in the majority of patients was feasible, with acceptable late morbidity and improved prognosis, particularly in patients with previous resection of recurrent tumours.

Reirradiation with Alternating Docetaxel-Based Chemotherapy for Recurrent Head and Neck Squamous Cell Carcinoma

Purpose:To report follow-up data and results of a dose escalation within a prospective phase II protocol scheduling alternating chemoreirradiation for patients with unresectable locoregional recurrence of head and neck cancer after previous curative-intent radiotherapy.Patients and Methods:Chemoreirradiation was initially performed in 27 patients by 40.0 Gy split-course reirradiation (re-RT) alternating with three cycles of docetaxel 50 mg/m2 day 1 and cisplatin 15 mg/m2 days 2–5 (first cohort). From 2002 onward, 30 consecutively treated patients received a late-course concomitant boost to 49.6 Gy (second cohort). In July 2008, the survival outcome was analyzed separately for both cohorts and the entire collective (n = 57).Results:The Kaplan-Meier estimates for 1- and 2-year overall survival (OS) were 52% and 24%, respectively (median OS 13.4 months). The median time of locoregional control was 9.6 months, and the actuarial 2-year freedom from distant metastasis rate was 55%. The re-RT dose escalation led to a significant improvement of the median OS (17.4 vs. 9.4 months; p = 0.039). Irrespective of the cohort, severe treatment-related toxicities occurred in about one third of patients.Conclusion:The treatment results confirm the efficacy and the safety of escalated re-RT doses in this chemoreirradiation protocol.ZusammenfassungZiel:Berichtet werden das Follow-up einer Phase-II-Studie zur alternierenden Reradiochemotherapie lokoregional rezidivierender, inoperabler HNO-Plattenepithelkarzinome sowie die Auswirkungen der in ihrem Rahmen erfolgten Dosiseskalation.Patienten und Methodik:Das ursprüngliche Therapieprotokoll umfasste drei Zyklen Chemotherapie (Docetaxel 50 mg/m2 Tag 1, Cisplatin 15 mg/m2 Tage 2–5) in den Wochen 1, 5 und 7, alternierend mit einer „split-course“-Rebestrahlung bis 40,0 Gy (täglich 2,0 Gy in den Wochen 2 + 3 und 5 + 6). Nach einer Zwischenauswertung im Jahr 2002 (erste Kohorte, n = 27) erhielten weitere 30 Patienten (zweite Kohorte) in Woche 6 einen konkomitanten Boost bis 49,6 Gy. Im Juli 2008 wurden die Studienendpunkte separat für beide Kohorten sowie für das Gesamtkollektiv (n = 57) analysiert.Ergebnisse:Im Gesamtkollektiv betrugen das 1- und 2-Jahres-Überleben 52% und 24% (medianes Überleben 13,4 Monate). Die mediane lokoregionale Kontrolle lag bei 9,6 Monaten, und nach 2 Jahren waren 55% der Patienten metastasenfrei. Die Dosiseskalation in der zweiten Kohorte führte zu einem signifikant verbesserten Gesamtüberleben (17,4 vs. 9,4 Monate; p = 0,039). Etwa ein Drittel der Patienten erlitt schwere behandlungsassoziierte Toxizitäten, und dies war unabhängig von der Patientenkohorte.Schlussfolgerung:Die Behandlungsergebnisse bestätigen die Effektivität und Sicherheit einer Dosiseskalation im Rahmen dieses Therapieprotokolls.