Reduced diffusion in normal appearing white matter of glioma patients following radio(chemo)therapy.

BACKGROUND AND PURPOSE: Standard treatment of high grade gliomas includes gross tumour resection followed by radio(chemo)therapy. Radiotherapy inevitably leads to irradiation of normal brain tissue. The goal of this prospective, longitudinal study was to use MRI to quantify normal appearing white and grey matter changes following radiation treatment as a function of dose and time after radiotherapy. MATERIALS AND METHODS: Pre-radiotherapy (proton or photon therapy) MRI and follow-up MRIs collected in 3 monthly intervals thereafter were analysed for 22 glioma patients and included diffusion tensor imaging, quantitative T1, T2* and proton density mapping. Abnormal tissue was excluded from analysis. MR signal changes were quantified within different dose bin regions for grey and white matter and subsequently for whole brain white matter. RESULTS: We found significant reductions in mean diffusivity, radial diffusivity, axial diffusivity and T2* in normal appearing white matter regions receiving a radiation dose as low as 10-20 Gy within the observational period of up to 18 months. The magnitude of these changes increased with the received radiation dose and progressed with time after radiotherapy. Whole brain white matter also showed a significant reduction in radial diffusivity as a function of radiation dose and time after radiotherapy. No significant changes were observed in grey matter. CONCLUSION: Diffusion tensor imaging and T2* imaging revealed normal appearing white matter changes following radiation treatment. The changes were dose dependant and progressed over time. Further work is needed to understand the underlying tissue changes and to correlate the observed diffusion changes with late brain malfunctions.

PORTAF - postoperative radiotherapy of non-small cell lung cancer: accelerated versus conventional fractionation - study protocol for a randomized controlled trial.

BACKGROUND: In early-stage non-small cell lung cancer (NSCLC) without affected lymph nodes detected at staging, surgical resection is still the mainstay of treatment. However, in patients with metastatic mediastinal lymph nodes (pN2) or non-radically resected primary tumors (R1/R2), postoperative radiotherapy (possibly combined with chemotherapy) is indicated. So far, investigations about time factors affecting postoperative radiotherapy have only examined the waiting time defined as interval between surgery and start of radiotherapy, but not the overall treatment time (OTT) itself. Conversely, results from trials on primary radio(chemo)therapy in NSCLC show that longer OTT correlates with significantly worse local tumor control and overall survival rates. This time factor of primary radio(chemo)therapy is thought to mainly be based on repopulation of surviving tumor cells between irradiation fractions. It remains to be elucidated if such an effect also occurs when patients with NSCLC are treated with postoperative radiotherapy after surgery (and chemotherapy). Our own retrospective data suggest an advantage of shorter OTT also for postoperative radiotherapy in this patient group. METHODS/DESIGN: This is a multicenter, prospective randomized trial investigating whether an accelerated course of postoperative radiotherapy with photons or protons (7 fractions per week, 2 Gy fractions) improves locoregional tumor control in NSCLC patients in comparison to conventional fractionation (5 fractions per week, 2 Gy fractions). Target volumes and total radiation doses will be stratified in both treatment arms based on individual risk factors. DISCUSSION: For the primary endpoint of the study we postulate an increase in local tumor control from 70% to 85% after 36 months. Secondary endpoints are overall survival of patients; local recurrence-free and distant metastases-free survival after 36 months; acute and late toxicity and quality of life for both treatment methods. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02189967 . Registered on 22 May 2014.

Radiochemotherapy-induced changes of tumour vascularity and blood supply estimated by dynamic contrast-enhanced CT and fractal analysis in malignant head and neck tumours.

OBJECTIVE: To investigate radiochemotherapy (RChT)-induced changes of transfer coefficient (K(trans)) and relative tumour blood volume (rTBV) estimated by dynamic contrast-enhanced CT (DCE-CT) and fractal analysis in head and neck tumours (HNTs). METHODS: DCE-CT was performed in 15 patients with inoperable HNTs before RChT, and after 2 and 5 weeks. The dynamics of K(trans) and rTBV as well as lacunarity, slope of log(lacunarity) vs log(box size), and fractal dimension were compared with tumour behaviour during RChT and in the 24-month follow-up. RESULTS: In 11 patients, an increase of K(trans) and/or rTBV after 20 Gy followed by a decrease of both parameters after 50 Gy was noted. Except for one local recurrence, no tumour residue was found during the follow-up. In three patients with partial tumour reduction during RChT, a decrease of K(trans) accompanied by an increase in rTBV between 20 and 50 Gy was detected. In one patient with continuous elevation of both parameters, tumour progressed after RChT. Pre-treatment difference in intratumoral heterogeneity with its decline under RChT for the responders vs non-responders was observed. CONCLUSION: Initial growth of K(trans) and/or rTBV followed by further reduction of both parameters along with the decline of the slope of log(lacunarity) vs log(box size) was associated with positive radiochemotherapeutic response. Increase of K(trans) and/or rTBV under RChT indicated a poor outcome. ADVANCES IN KNOWLEDGE: The modification of K(trans) and rTBV as measured by DCE-CT may be applied for the assessment of tumour sensitivity to chose RChT regimen and, consequently, to reveal clinical impact allowing individualization of RChT strategy in patients with HNT.

Potential clinical predictors of outcome after postoperative radiotherapy of non-small cell lung cancer.

AIM: The aim of this analysis was to investigate the impact of tumour-, treatment- and patient-related cofactors on local control and survival after postoperative adjuvant radiotherapy in patients with non-small cell lung cancer (NSCLC), with special focus on waiting and overall treatment times. PATIENTS AND METHODS: For 100 NSCLC patients who had received postoperative radiotherapy, overall, relapse-free and metastases-free survival was retrospectively analysed using Kaplan-Meier methods. The impact of tumour-, treatment- and patient-related cofactors on treatment outcome was evaluated in uni- and multivariate Cox regression analysis. RESULTS: No statistically significant difference between the survival curves of the groups with a short versus a long time interval between surgery and radiotherapy could be shown in uni- or multivariate analysis. Multivariate analysis revealed a significant decrease in overall survival times for patients with prolonged overall radiotherapy treatment times exceeding 42 days (16 vs. 36 months) and for patients with radiation-induced pneumonitis (8 vs. 29 months). CONCLUSION: Radiation-induced pneumonitis and prolonged radiation treatment times significantly reduced overall survival after adjuvant radiotherapy in NSCLC patients. The negative impact of a longer radiotherapy treatment time could be shown for the first time in an adjuvant setting. The hypothesis of a negative impact of longer waiting times prior to commencement of adjuvant radiotherapy could not be confirmed.

Modification of staging and treatment of head and neck cancer by FDG-PET/CT prior to radiotherapy.

BACKGROUND AND PURPOSE: Reliable tumor staging is a fundamental pre-requisite for efficient tumor therapy and further prognosis. The aim of this study was to compare head and neck cancer (HNC) staging before and after FDG-PET/CT, evaluating the stage modifications for radiotherapy (RT) planning. PATIENTS AND METHODS: A total of 102 patients with untreated primary HNC, who underwent conventional staging and staging including FDG-PET/CT before RT, were enrolled in this retrospective study. Blinded pre-FDG-PET/CT and post-FDG-PET/CT staging data were compared. The impact on patient management was tested by comparing the intention before and after FDG-PET/CT. RESULTS: Significant modifications of T, N, and M stage as well as clinical stage were detected after inclusion of FDG-PET/CT data (p = 0.002, 0.0006, 0.001, 0.03, respectively). Overall, the implementation of FDG-PET/CT led to modification of RT intention decision in 14 patients. CONCLUSIONS: FDG-PET/CT demonstrates essential influence on tumor staging in HNC patients scheduled for irradiation. Implementation of FDG-PET/CT in imaging protocol improves selection of candidates for curative and palliative RT and allows further optimization of treatment management and therapy intention.

Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC).

BACKGROUND: Continuous hyperfractionated accelerated radiotherapy (CHART) counteracts repopulation and may significantly improve outcome of patients with non-small-cell lung cancer (NSCLC). Nevertheless high local failure rates call for radiation dose escalation. We report here the final results of the multicentric CHARTWEL trial (CHART weekend less, ARO 97-1). PATIENTS AND METHODS: Four hundred and six patients with NSCLC were stratified according to stage, histology, neoadjuvant chemotherapy and centre and were randomized to receive 3D-planned radiotherapy to 60Gy/40 fractions/2.5weeks (CHARTWEL) or 66Gy/33 fractions/6.5weeks (conventional fractionation, CF). RESULTS: Overall survival (OS, primary endpoint) at 2, 3 and 5yr was not significantly different after CHARTWEL (31%, 22% and 11%) versus CF (32%, 18% and 7%; HR 0.92, 95% CI 0.75-1.13, p=0.43). Also local tumour control rates and distant metastases did not significantly differ. Acute dysphagia and radiological pneumonitis were more pronounced after CHARTWEL, without differences in clinical signs of pneumopathy. Exploratory analysis revealed a significant trend for improved LC after CHARTWEL versus CF with increasing UICC, T or N stage (p=0.006-0.025) and after neoadjuvant chemotherapy (HR 0.48, 0.26-0.89, p=0.019). CONCLUSIONS: Overall, outcome after CHARTWEL or CF was not different. The lower total dose in the CHARTWEL arm was compensated by the shorter overall treatment time, confirming a time factor for NSCLC. The higher efficacy of CHARTWEL versus CF in advanced stages and after chemotherapy provides a basis for further trials on treatment intensification for locally advanced NSCLC.

MR perfusion measurement of contrast uptaking lesions: consideration of T2* shortening due to interstitial contrast agent.

AIM: In MR perfusion measurements of contrast uptaking lesions, time intensity curves are hampered by T 1 shortening as well as by the change of T 2 * due to interstitial contrast material (CM). Using double echo sequences, the influence of T 1 can be mathematically eliminated. For correction of the T 2 * influence an empirical algorithm using time-intensity-curves exclusively measured in the suspected lesion is proposed. METHODS: The interstitial CM concentration is assumed to be proportional to the change of the intensity for T E = 0 or to the change of the relaxation rate DeltaR 1 respectively. The intravascular CM concentration is estimated from DeltaR 2 *. It is adjusted to zero for a time point sufficiently late after the bolus injection by subtraction of the interstitial concentration. This method was applied to double echo FLASH measurements on 15 pharyngeal tumors. RESULTS: The proposed correction transforms the time dependence of the estimated intravascular CM concentration into a plausible course. CONCLUSION: Double echo perfusion measurements can be corrected for the interstitial CM induced T 2 * shortening without additional measurements with proneness to errors. This does not necessarily improve the diagnostic value, since possibly "implied multivariate aspects" of uncorrected parameters (here: contrast uptake of the lesion is related to tumor neoangiogenesis as well) are eliminated.

Dose and fractionation concepts in the primary radiotherapy of non-small cell lung cancer.

At present, radiotherapy alone or in combination with chemotherapy offers the only chance of cure of medically inoperable or locally advanced unresectable non-small cell lung cancer. The radiobiological basis and clinical results of current dose and fractionation concepts in the primary radiotherapy of NSCLC are briefly reviewed. Whenever possible, focus is given to the results of randomized phase III trials. With the exception of early disease treated to doses higher than 60 Gy, the prognosis of inoperable localized NSCLC is very poor. Local recurrence is the major cause of failure after radiation therapy calling for intensified local treatment. Dose-escalation using conventional fractionation or moderate hypofractionation is promising but randomized trials are presently not available. Dose-escalated hyperfractionation theoretically offers advantages, however, there appears currently no strong evidence from randomized trials supporting this approach in NSCLC. The highly accelerated CHART regimen significantly improved survival by 9% compared to standard radiotherapy. Nevertheless, even when treated with CHART, about 80% of all patients will eventually develop local recurrence and 60% distant metastases. Many trials on combined radiochemotherapy have used radiotherapy regimens that are not optimal from a current perspective. Because of the high rate of both, local recurrence and distant metastases, future research should be directed to further intensify radiotherapy as well as to integrate such protocols with systemic treatment in carefully selected patients. Since toxicity is expected to increase, state-of-the-art 3D conformal radiation techniques need to be part of clinical trials testing such strategies.

Radiobiological hypoxia, oxygen tension, interstitial fluid pressure and relative viable tumour area in two human squamous cell carcinomas in nude mice during fractionated radiotherapy.

Very little is known about the correlation between the radiobiological hypoxic fraction (rHF) and other measures of tumour oxygenation during fractionated irradiation. In the present study the rHF is determined in untreated human FaDu and GL squamous cell carcinoma in nude mice and in tumours irradiated with 10 fractions in 2 weeks and 20 fractions in 4 weeks, using tumour control as the experimental endpoint. The results were compared with measurements of the pO2, the interstitial fluid pressure (IFP) and the relative viable tumour area. In FaDu tumours the radiobiological hypoxic fractions (rHFs) before and during irradiation were not statistically different from 100%. Depending on the assumptions made for D0, the rHFs of GL tumours were between 0.2 and 4% or 30 and 53%. The median pO2 values were 2.8 mmHg for untreated FaDu tumours and 0.2 mmHg for GL tumours (p < 0.001). The median IFP values were 2.6 mmHg in FaDu and 5.3 mmHg in GL tumours (p = 0.01). No important changes in the pO2 and IFP values were observed during fractionated irradiation. The relative viable tumour area during irradiation decreased by 83% in FaDu tumours (p = 0.002) and by 54% in GL tumours (p = 0.003). It is concluded that differences in rHF exist between FaDu and GL tumours before and during fractionated irradiation and that these differences are not reflected by pO2 and IFP values and the relative viable tumour area.

Lack of effect of small high-dose volumes on the dose-response relationship for the development of fibrosis in distant parts of the ipsilateral lung in mini-pigs.

PURPOSE: Multi-field radiation therapy for intrathoracic tumours results in a heterogeneous dose distribution in lung tissue. This study investigated whether irradiation of small lung volumes with high fibrogenic doses affects the dose-response relationship for development of fibrosis in distant parts of the ipsilateral lung of mini-pigs. MATERIALS AND METHODS: The whole right lung of 26 'Mini-Lewe' pigs was irradiated with homogeneous doses of between 25 Gy and 40 Gy given in five equal fractions using opposing anterior-posterior portals and a linear accelerator. Another 32 animals were irradiated with a constant dose of 35 Gy to a small house-shaped high-dose field (base 3.0 cm, height 4 cm) located 3 cm caudolateral to the right hilus, while the surrounding right lung received either no irradiation or homogeneous doses of between 20 Gy and 30 Gy. The radiation fields were simulated and port films were obtained for each of the 10 fields in all pigs. Fibrosis was quantified 9 months after irradiation by determination of the hydroxyproline (HP) content of the 32 high-dose volumes and in the lung apex and the basolateral lung of all 58 pigs. Based on the reference value for the HP-ratio, i.e. the HP-concentration of the right lung over the left lung, obtained in 12 unirradiated control animals, the experimental results were converted into quantal data for probit analysis, a responder being an animal with an HP-ratio > 1.33. RESULTS: A dose-response relationship for the HP-ratio was obtained in the different lung sites and irradiation groups. For a given dose level the mean HP-ratios and response rates did not differ systematically between the lung apex and the basolateral lung. Probit analysis of the pooled data produced ED50 values of 21.8 Gy (95% CI 12-37) for irradiation without a high-dose volume and 25.9 Gy (24-28) for irradiation with a high-dose volume. These values are not significantly different. The results from both irradiation groups could be well fitted by a common dose-response curve with an ED50 value of 26.1 Gy. Unexpectedly, the response rates in the high-dose volume increased with increasing dose to the surrounding right lung. Analysis of the port films provided an explanation for this finding: inaccuracies in daily field positioning. When this error was corrected for by use of the mean dose to the high-dose volume, a dose-response curve with an ED50 of 25.2 Gy (22-29) was determined for the high-dose volume. CONCLUSIONS: The results of the study indicate that the irradiation of a small lung volume with high fibrogenic doses does not affect the dose-response relationship for development of fibrosis in distant parts of the ipsilateral lung.

Down-regulation of SP1 DNA binding activity in the process of radiation-induced pulmonary fibrosis.

PURPOSE: To determine changes in the expression and function of the transcription factor SP1 in radiation-induced pulmonary fibrosis. MATERIALS AND METHODS: The right lungs of female Fischer rats were irradiated with a fibrogenic single dose of 20 Gy gamma-irradiation. SP1 mRNA and protein expression was determined by Northern and Western blotting, respectively, between 30 min and 12 weeks after irradiation. Cellular localization of SP1 protein was characterized by immunohistochemistry (peroxidase labelling). SP1 DNA binding activity was studied with electrophoretic mobility shift assays (EMSA). RESULTS: Eight weeks after irradiation, pulmonary fibrosis was first observed. SP1 DNA binding activity showed a short-term increase from 30 min to 12 h after irradiation. Thereafter it remained quite stable until 1 month after irradiation. However, 2 months after irradiation, SP1 DNA binding activity was no longer detectable. The SP1 mRNA level was not reduced at this time, nor was there a reduction in its size. However, Western blotting revealed the occurrence of at least two slightly smaller additional bands 2 months after irradiation whereas the original SP1 band vanished. This suggests a degradation event of SP1 taking place near one or both ends of the protein. Most of the SP1 protein was found in type II pneumocytes and alveolar macrophages of the normal and fibrotic lung. Bronchial epithelial cells were also positive. In the fibrotic lung, proliferating fibroblasts also become positive. CONCLUSIONS: The functional knockout of the transcription factor SP1, in the process of irradiation-induced pulmonary fibrosis, is demonstrated. This should help elucidate the severe disturbances in transcriptional regulation, cellular proliferation and differentiation occurring in the lung at long intervals after irradiation.

Response of pig lung to irradiation with accelerated 12C-ions.

The response of pig lungs to irradiation with 12C-ions was assessed in two experiments to validate the procedures for heavy ion therapy planning at the Gesellschaft für Schwerionenforschung (GSI) and to explore their range of applicability. In both experiments, the target volume (spread-out Bragg peak, SOBP) was planned to be a 4 cm long cylinder with a diameter of 4 cm. Doses in the SOBP were prescribed to be equivalent to 5x4 Gy, 5x5.5 Gy and 5x7 Gy of x-rays in the first experiment, and to 5 fractions of 7 Gy and 9 Gy in the second experiment. The lung response in the first experiment was less than expected on the basis of earlier experiments with photons. Pneumonitis reaction and chronic fibrotic changes were observed outside the prescribed high-dose region. In the second experiment, the effects were more pronounced than had been expected on the basis of the first experiment. Changes were most intense in the high-dose region, but were also seen throughout the lung along the beam channel. Moreover, significant skin reactions were observed at the beam entrance site in all animals and - less pronounced - at the beam exit site in 3 of the 6 animals. In conclusion, the complex irradiation geometry of the pig lung, the changes of body weight between the two experiments, and insufficient accounting for a change in the relative biological effectiveness (RBE) computation led to substantial deviations of the observed reactions from expectations, the reasons for which could be identified in a subsequent analysis. The less pronounced lung reaction in the first experiment was due to an overestimation of RBE in a preliminary version of the algorithm for its determination. The extension of the fibrotic reaction resulted from the smear-out of the high-dose region due to density variations in tissue structures, respiratory movement, and limited positioning accuracy. The skin reactions at the entrance port reflect the different treatment geometry in the two experiments. The one unexplained observation is the mild skin reaction that was observed in the second experiment at the beam exit site.

[Results of irradiation of inoperable stage III non-small cell lung cancer with 25Gy in five fractions]. / Ergebnisse der Bestrahlung inoperabler nichtkleinzelliger Bronchialkarzinome im Stadium III mit 25 Gy in fünf Fraktionen.

BACKGROUND: Patients with advanced Stage III inoperable non-small cell lung cancer who were not suitable for irradiation with curative doses, were treated at the Department of Radiotherapy of the University Hospital of Dresden with 25 Gy in 5 fractions over 1 to 2 weeks. Survival of these patients was compared in this retrospective study to the survival of patients treated during the same period with 60 Gy in 30 fractions. PATIENTS AND METHOD: Between 1985 and 1994 298 patients were treated for a histologically or cytologically proven non-small cell lung carcinoma with 60 Gy in 30 fractions (n = 80), with 40 Gy in 20 fractions (n = 26) or with 25 Gy in 5 fractions (n = 192). Overall survival was determined using actuarial methods. Prognostic parameters were analyzed using uni- and multivariate tests. RESULTS: Median overall survival for all patients was 6 months (95% confidence interval 5; 7). In univariate analysis, survival of the patients treated with 60 Gy was significantly better than survival in the other groups. Median survival was 11 months (9; 13) after 60 Gy, 6 months (4; 8) after 40 Gy and 5 months (4; 6) after 25 Gy. In multivariate analysis the treatment schedule lost its significant influence on outcome of the therapy. The most important prognostic parameter was the performance status of the patients. CONCLUSIONS: When stratified for performance status as the most important prognostic parameter the survival time after hypofractionated irradiation to 25 Gy given in 5 fractions in 1 to 2 weeks was not significantly different from the results after conventional fractionation to 60 Gy. Hypofractionated radiation schedules are often more convenient for the patient, economical, and have been shown to be effective in symptom control. Thus, in clear palliative situations hypofractionated treatment with 25 Gy in 5 fractions or a comparable schedule appears to be a reasonable therapeutic option.

Comparison of the response of human FaDu squamous cell carcinoma in nude mice after hypofractionated-accelerated regimens and "curative" fractionation schedules.

BACKGROUND: It has been suggested that tumors respond differently after irradiation with 10 or more fractions than with less fractionated regimens and that extrapolation from experiments with only a few fractions to "curative" regimens may be invalid. To test this hypothesis, we compared hypofractionated-accelerated treatments with "curative" fractionation schedules in human squamous cell carcinoma in nude mice. MATERIAL AND METHODS: FaDu tumors were transplanted subcutaneously into the hindleg of NMRI nu/nu mice. TCD50 values, i.e., the dose necessary to control 50% of the tumors locally, were determined after irradiation under ambient blood flow conditions with 5 and 10 fractions in 5 days, 10 fractions in 10 days, and 30 fractions in 15 days, 6 weeks or 10 weeks. RESULTS: TCD50 values of the hypofractionated regimens were not significantly different and varied from 41 to 46 Gy. The number of fractions given in the same overall time had no measurable effect on local tumor control. The TCD50 after 30 fractions in 6 weeks was 30 Gy higher than after the hypofractionated regimens. This effect was caused by a substantial increase of TCD50 with overall treatment time, the dose recovered per day was 0.82 Gy (95% CI 0.66; 0.96). alpha/beta eff determined from all data was 58 Gy (13; infinite). CONCLUSIONS: The results of the present study compare well with our previous findings after different "curative" fractionation schedules in the same tumor. Thus, our study does not support that tumors respond differently after application of 10 or more fractions compared to less fractionated regimens. The biological mechanisms that govern the radiation response of FaDu tumors appear to be the same for hypofractionated-accelerated and "curative" regimens. Since only one tumor was investigated, these results cannot be generalized at the present time.

[Radiation tolerance of the human spinal cord]. / Strahlentoleranz des menschlichen Rückenmarks.

PURPOSE: Chronic myelopathy is among the most serious sequelae of high dose radiation treatment. Therefore medical and forensic reasons warrant detailed knowledge of the radiation tolerance of the human spinal cord. PATIENTS AND METHODS: This paper reviews published data on the incidence of radiation myelopathy in patients treated with megavoltage radiation. RESULTS AND CONCLUSIONS: Two years after completion of radiation treatment with daily fractions of approximately 2 Gy development of radiation myelopathy is expected in 1% of the patients at 50 to 55 Gy. An incidence of 5% is estimated to occur at approximately 55 to 60 Gy. At higher doses the risk of spinal cord damage increases steeply. Interpretation of these data has to consider that the incidence of radiation myelopathy increases with increasing time of follow-up. Even after two years no clearcut plateau is observed. High doses per fraction are poorly tolerated by the spinal cord, the alpha/beta-ratio appears to be approximately 1 Gy. Accelerated schedules with < or = 2 Gy per fraction but daily doses greatly exceeding 2 Gy may result in a higher risk of radiation myelopathy than conventionally fractionated treatments. This observation seems, at least in part, to be due to a slow component of repair of sublethal radiation damage in the spinal cord.