Annekatrin Seidlitz

Glioblastoma multiforme: emerging treatments and stratification markers beyond new drugs

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults. The standard therapy for GBM is maximal surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ). In spite of the extensive treatment, the disease is associated with poor clinical outcome. Further intensification of the standard treatment is limited by the infiltrating growth of the GBM in normal brain areas, the expected neurological toxicities with radiation doses >60 Gy and the dose-limiting toxicities induced by systemic therapy. To improve the outcome of patients with GBM, alternative treatment modalities which add low or no additional toxicities to the standard treatment are needed. Many Phase II trials on new chemotherapeutics or targeted drugs have indicated potential efficacy but failed to improve the overall or progression-free survival in Phase III clinical trials. In this review, we will discuss contemporary issues related to recent technical developments and new metabolic strategies for patients with GBM including MR (spectroscopy) imaging, (amino acid) positron emission tomography (PET), amino acid PET, surgery, radiogenomics, particle therapy, radioimmunotherapy and diets.

Residual tumour hypoxia in head-and-neck cancer patients undergoing primary radiochemotherapy, final results of a prospective trial on repeat FMISO-PET imaging

BACKGROUND Hypoxia is a well recognised parameter of tumour resistance to radiotherapy, a number of anticancer drugs and potentially immunotherapy. In a previously published exploration cohort of 25 head and neck squamous cell carcinoma (HNSCC) patients on [18F]fluoromisonidazole positron emission tomography (FMISO-PET) we identified residual tumour hypoxia during radiochemotherapy, not before start of treatment, as the driving mechanism of hypoxia-mediated therapy resistance. Several quantitative FMISO-PET parameters were identified as potential prognostic biomarkers. Here we present the results of the prospective validation cohort, and the overall results of the study. METHODS FMISO-PET/CT images of further 25 HNSCC patients were acquired at four time-points before and during radiochemotherapy (RCHT). Peak standardised uptake value, tumour-to-background ratio, and hypoxic volume were analysed. The impact of the potential prognostic parameters on loco-regional tumour control (LRC) was validated by the concordance index (ci) using univariable and multivariable Cox models based on the exploration cohort. Log-rank tests were employed to compare the endpoint between risk groups. RESULTS The two cohorts differed significantly in several baseline parameters, e.g., tumour volume, hypoxic volume, HPV status, and intercurrent death. Validation was successful for several FMISO-PET parameters and showed the highest performance (ci=0.77-0.81) after weeks 1 and 2 of treatment. Cut-off values for the FMISO-PET parameters could be validated after week 2 of RCHT. Median values for the residual hypoxic volume, defined as the ratio of the hypoxic volume in week 2 of RCHT and at baseline, stratified patients into groups of significantly different LRC when applied to the respective other cohort. CONCLUSION Our study validates that residual tumour hypoxia during radiochemotherapy is a major driver of therapy resistance of HNSCC, and that hypoxia after the second week of treatment measured by FMISO-PET may serve as biomarker for selection of patients at high risk of loco-regional recurrence after state-of-the art radiochemotherapy.

Early and late effects of radiochemotherapy on cerebral blood flow in glioblastoma patients measured with non-invasive perfusion MRI.

BACKGROUND AND PURPOSE To provide a systematic measure of changes of brain perfusion in healthy tissue following a fractionated radiotherapy of brain tumors. MATERIALS AND METHODS Perfusion was assessed before and after radiochemotherapy using arterial spin labeling in a group of 24 patients (mean age 54.3 ± 14.1 years) with glioblastoma multiforme. Mean relative perfusion change in gray matter in the hemisphere contralateral to the tumor was obtained for the whole hemisphere and also for six regions created by thresholding the individual dose maps at 10 Gy steps. RESULTS A significant decrease of perfusion of -9.8 ± 20.9% (p=0.032) compared to the pre-treatment baseline was observed 3 months after the end of radiotherapy. The decrease was more pronounced for high-dose regions above 50 Gy (-16.8 ± 21.0%, p=0.0014) than for low-dose regions below 10 Gy (-2.3 ± 20.0%, p=0.54). No further significant decrease compared to the post-treatment baseline was observed 6 months (-0.4 ± 18.4%, p=0.94) and 9 months (2.0 ± 15.4%, p=0.74) after the end of radiotherapy. CONCLUSIONS Perfusion decreased significantly during the course of radiochemotherapy. The decrease was higher in regions receiving a higher dose of radiation. This suggests that the perfusion decrease is at least partly caused by radiotherapy. Our results suggest that the detrimental effects of radiochemotherapy on perfusion occur early rather than later.

Photon vs. proton radiochemotherapy: Effects on brain tissue volume and perfusion

BACKGROUND AND PURPOSE To compare the structural and hemodynamic changes of healthy brain tissue in the cerebral hemisphere contralateral to the tumor following photon and proton radiochemotherapy. MATERIALS AND METHODS Sixty-seven patients (54.9 ±14.0 years) diagnosed with glioblastoma undergoing adjuvant photon (n = 47) or proton (n = 19) radiochemotherapy with temozolomide after tumor resection underwent T1-weighted and arterial spin labeling MRI. Changes in volume and perfusion before and 3 to 6 months after were compared between therapies. RESULTS A decrease in gray matter (GM) (-2.2%, P<0.001) and white matter (WM) (-1.2%, P<0.001) volume was observed in photon-therapy patients compared to the pre-radiotherapy baseline. In contrast, for the proton-therapy group, no significant differences in GM (0.3%, P = 0.64) or WM (-0.4%, P = 0.58) volume were observed. GM volume decreased with 0.9% per 10 Gy dose increase (P<0.001) and differed between the radiation modalities (P<0.001). Perfusion decreased in photon-therapy patients (-10.1%, P = 0.002), whereas the decrease in proton-therapy patients, while comparable in magnitude, did not reach statistical significance (-9.1%, P = 0.12). There was no correlation between perfusion decrease and either dose (P = 0.64) or radiation modality (P = 0.94). CONCLUSIONS Our results show that the tissue volume decrease depends on radiation dose delivered to the healthy hemisphere and differs between treatment modalities. In contrast, the decrease in perfusion was comparable for both irradiation modalities. We conclude that proton therapy may reduce brain-volume loss when compared to photon therapy.

FMISO-PET-based lymph node hypoxia adds to the prognostic value of tumor only hypoxia in HNSCC patients

PURPOSE This secondary analysis of the prospective study on repeat [18F]fluoromisonidazole (FMISO)-PET in patients with locally advanced head and neck squamous cell carcinomas (HNSCC) assessed the prognostic value of synchronous hypoxia in primary tumor (Tu) and lymph node metastases (LN), and evaluated whether the combined reading was of higher prognostic value than that of primary tumor hypoxia only. METHODS This analysis included forty-five LN-positive HNSCC patients. FMISO-PET/CTs were performed at baseline, weeks 1, 2 and 5 of radiochemotherapy. Based on a binary scale, Tu and LN were categorized as hypoxic or normoxic, and two prognostic parameters were defined: Tu-hypoxia (independent of the LN oxygenation status) and synchronous Tu-and-LN-hypoxia. In fifteen patients with large LN (N = 21), additional quantitative analyses of FMISO-PET/CTs were performed. Imaging parameters at different time-points were correlated to the endpoints, i.e., locoregional control (LRC), local control (LC), regional control (RC) and time to progression (TTP). Survival curves were estimated using the cumulative incidence function. Univariable and multivariable Cox regression was used to evaluate the prognostic impact of hypoxia on the endpoints. RESULTS Synchronous Tu-and-LN-hypoxia was a strong adverse prognostic factor for LC, LRC and TTP at any of the four time-points (p ≤ 0.004), whereas Tu-hypoxia only was significantly associated with poor LC and LRC in weeks 2 and 5 (p ≤ 0.047), and with TTP in week 1 (p = 0.046). The multivariable analysis confirmed the prognostic value of synchronous Tu-and-LN-hypoxia regarding LRC (HR = 14.8, p = 0.017). The quantitative FMISO-PET/CT parameters correlated with qualitative hypoxia scale and RC (p < 0.001, p ≤ 0.033 at week 2, respectively). CONCLUSIONS This secondary analysis suggests that combined reading of primary tumor and LN hypoxia adds to the prognostic information of FMSIO-PET in comparison to primary tumor assessment alone in particular prior and early during radiochemotherapy. Confirmation in ongoing trials is needed before using this marker for personalized radiation oncology.

Independent validation of a new reirradiation risk score (RRRS) for glioma patients predicting post-recurrence survival: A multicenter DKTK/ROG analysis

BACKGROUND AND PURPOSE Reirradiation (reRT) is a valid option with considerable efficacy in patients with recurrent high-grade glioma, but it is still not known which patients might be optimal candidates for a second course of irradiation. This study validated a newly developed prognostic score independently in an external patient cohort. MATERIAL AND METHODS The reRT risk score (RRRS) is based on a linear combination of initial histology, clinical performance status, and age derived from a multivariable model of 353 patients. This score can predict post-recurrence survival (PRS) after reRT. The validation dataset consisted of 212 patients. RESULTS The RRRS differentiates three prognostic groups. Discrimination and calibration were maintained in the validation group. Median PRS times in the development cohort for the good/intermediate/poor risk categories were 14.2, 9.1, and 5.3 months, respectively. The respective groups within the validation cohort displayed median PRS times of 13.8, 8.8, and 3.8 months, respectively. Unos C for development data was 0.64 (CI: 0.60-0.69) and for validation data 0.63 (CI: 0.58-0.68). CONCLUSIONS The RRRS has been successfully validated in an independent patient cohort. This linear combination of three easily determined clinicopathological factors allows for a reliable classification of patients and may be used as stratification factor for future trials.

Re‐irradiation of recurrent gliomas: pooled analysis and validation of an established prognostic score—report of the Radiation Oncology Group (ROG) of the German Cancer Consortium (DKTK)

The heterogeneity of high‐grade glioma recurrences remains an ongoing challenge for the interdisciplinary neurooncology team. Response to re‐irradiation (re‐RT) is heterogeneous, and survival data depend on prognostic factors such as tumor volume, primary histology, age, the possibility of reresection, or time between primary diagnosis and initial RT and re‐RT. In the present pooled analysis, we gathered data from radiooncology centers of the DKTK Consortium and used it to validate the established prognostic score by Combs et al. and its modification by Kessel et al. Data consisted of a large independent, multicenter cohort of 565 high‐grade glioma patients treated with re‐RT from 1997 to 2016 and a median dose of 36 Gy. Primary RT was between 1986 and 2015 with a median dose of 60 Gy. Median age was 54 years; median follow‐up was 7.1 months. Median OS after re‐RT was 7.5, 9.5, and 13.8 months for WHO IV, III, and I/II gliomas, respectively. All six prognostic factors were tested for their significance on OS. Aside from the time from primary RT to re‐RT (P = 0.074) and the reresection status (P = 0.101), all factors (primary histology, age, KPS, and tumor volume) were significant. Both the original and new score showed a highly significant influence on survival with P < 0.001. Both prognostic scores successfully predict survival after re‐RT and can easily be applied in the routine clinical workflow. Now, further prognostic features need to be found to even improve treatment decisions regarding neurooncological interventions for recurrent glioma patients.