Mats Holmberg

Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial

The aim of this clinical trial was to investigate safety and efficacy when combining cetuximab with bevacizumab and irinotecan in patients with recurrent primary glioblastoma multiforme (GBM). Patients were included with recurrent primary GBM and progression within 6 months of ending standard treatment (radiotherapy and temozolomide). Bevacizumab and irinotecan were administered IV every 2 weeks. The first 10 patients received bevacizumab 5 mg/kg, but this was increased to 10 mg/kg after interim safety analysis. Irinotecan dose was based on whether patients were taking enzyme-inducing antiepileptic drugs or not: 340 and 125 mg/m(2), respectively. Cetuximab 400 mg/m(2) as loading dose followed by 250 mg/m(2) weekly was administered IV. Forty-three patients were enrolled in the trial, of which 32 were available for response. Radiographic responses were noted in 34%, of which 2 patients had complete responses and 9 patients had partial responses. The 6-month progression-free survival probability was 30% and median overall survival was 29 weeks (95% CI: 23-37 weeks). One patient had lacunar infarction, 1 patient had multiple pulmonary embolisms, and 3 patients had grade 3 skin toxicity, for which 1 patient needed plastic surgery. One patient was excluded due to suspicion of interstitial lung disease. Three patients had deep-vein thrombosis; all continued on study after adequate treatment. Cetuximab in combination with bevacizumab and irinotecan in recurrent GBM is well tolerated except for skin toxicity, with an encouraging response rate. However, the efficacy data do not seem to be superior compared with results with bevacizumab and irinotecan alone.

A phase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy

Abstract The combination of irinotecan and bevacizumab has shown efficacy in the treatment of recurrent glioblastoma multiforme (GBM). A prospective, phase II study of 85 patients with various recurrent brain tumors was carried out. Primary endpoints were progression free survival (PFS) and response rate. Material and methods. Patients with recurrent primary brain tumors with performance status 0–2 were eligible. Intravenous bevacizumab 10 mg/kg and irinotecan 125/340 mg/m2 were administered every 14 days. Evaluation was carried out every eight weeks using MRI and Macdonald response criteria. Treatment was continued until progression. Results. In total 85 patients were included with the following histologies: GBM (n = 32), glioma WHO gr. III (n = 33), glioma WHO gr. II (n = 12) and others (n = 8). Patients received a median of four cycles. ORR (overall response rate) for glioblastoma was 25% and 59% achieved stable disease (SD). Median PFS was 5.2 months. For grade III gliomas ORR was 21% and 45% had SD. Median PFS was 3.7 months. No objective responses occurred in grade II gliomas. In the non-glioma population, one PR as well as several long PFS times were observed. Discussion and conclusion. The combination of bevacizumab and irinotecan is well tolerated and moderately efficacious in glioblastoma and glioma WHO gr. III. A majority of patients achieve at least disease stabilization. Prolonged progression-free survival in non-glioma patients warrants further research.

MRI target delineation may reduce long-term toxicity after prostate radiotherapy

Abstract Background and purpose. Aiming for minimal toxicity after radical prostate cancer (PC) radiotherapy (RT), magnetic resonance imaging (MRI) target delineation could be a possible benefit knowing that clinical target volumes (CTV) are up to 30% smaller, when CTV delineation on MRI is compared to standard computed tomography (CT). This study compares long-term toxicity using CT or MRI delineation before PC RT. Material and methods. Urinary and rectal toxicity assessments 36 months after image-guided RT (78 Gy) using CTC-AE scores in two groups of PC patients. Peak symptom score values were registered. One group of patients (n = 72) had standard CT target delineation and gold markers as fiducials. Another group of patients (n = 73) had MRI target delineation and a nickel-titanium stent as fiducial. Results. At 36 months no difference in overall survival (92% in both groups, p = 0.29) or in PSA-relapse free survival was found between the groups (MRI = 89% and CT = 94%, p = 0.67). A significantly smaller CTV was found in the MRI group (p = 0.02). Urinary retention and frequency were significantly reduced in the MRI group (p = 0.03 in the matter of both). The overall urinary and rectal toxicity did not differ between the two groups. Conclusion. MRI delineation leads to a significantly reduced CTV. Significantly lower urinary frequency and urinary retention toxicity scores were observed following MRI delineation. The study did not find significant differences in overall urinary or rectal toxicity between the two groups. PSA-relapse survival did not differ between the two groups at 36 months.

Docetaxel rechallenge after an initial good response in patients with metastatic castration‐resistant prostate cancer

To evaluate the benefit of docetaxel rechallenge in patients with metastatic castration‐resistant prostate cancer (mCRPC) relapsing after an initial good response to first‐line docetaxel.

Differences in supratentorial white matter diffusion after radiotherapy - new biomarker of normal brain tissue damage?

Abstract Introduction. Therapy-induced injury to normal brain tissue is a concern in the treatment of all types of brain tumours. The purpose of this study was to investigate if magnetic resonance diffusion tensor imaging (DTI) could serve as a potential biomarker for the assessment of radiation-induced long-term white matter injury. Material and methods. DTI- and T1-weighted images of the brain were obtained in 19 former radiotherapy patients [nine men and 10 women diagnosed with astrocytoma (4), pituitary adenoma (6), meningioma (8) and craniopharyngioma (1), average age 57.8 (range 35–71) years]. Average time from radiotherapy to DTI scan was 4.6 (range 2.0–7.1) years. NordicICE software (NIC) was used to calculate apparent diffusion coefficient maps (ADC-maps). The co-registration between T1 images and ADC-maps were done using the auto function in NIC. The co-registration between the T1 images and the patient dose plans were done using the auto function in the treatment planning system Eclipse from Varian. Regions of interest were drawn on the T1-weighted images in NIC based on isocurves from Eclipse. Data was analysed by t-test. Estimates are given with 95% CI. Results. A mean ADC difference of 4.6(0.3;8.9)× 10−5 mm2/s, p = 0.03 was found between paired white matter structures with a mean dose difference of 31.4 Gy. Comparing the ADC-values of the areas with highest dose from the paired data (dose > 33 Gy) with normal white matter (dose < 5 Gy) resulted in a mean dose difference of 44.1 Gy and a mean ADC difference of 7.87(3.15;12.60)× 10−5 mm2/s, p = 0.003. Following results were obtained when looking at differences between white matter mean ADC in average dose levels from 5 to 55 Gy in steps of 10 Gy with normal white matter mean ADC: 5 Gy; 1.91(−1.76;5.58)× 10−5 mm2/s, p = 0.29; 15 Gy; 5.81(1.53;10.11)× 10−5 mm2/s, p = 0.01; 25 Gy; 5.80(2.43;9.18)× 10−5 mm2/s, p = 0.002; 35 Gy; 5.93(2.89;8.97)× 10−5 mm2/s, p = 0.0007; 45 Gy; 4.32(−0.24;8.89)× 10−5 mm2/s, p = 0.06; 55 Gy; −4.04(−14.96;6.89)× 10−5 mm2/s, p = 0.39. Conclusion. The results indicate that the structural integrity of white matter, assessed by ADC-values based on DTI, undergoes changes after radiation therapy starting as early as total dose levels between 5 and 15 Gy.

A comparison of morbidity following conformal versus intensity-modulated radiotherapy for urinary bladder cancer

Abstract Background. In radiotherapy (RT) of urinary bladder cancer, the use of intensity-modulated RT (IMRT) opens for sparing of considerable intestinal volumes. The purpose of the present study was to investigate the acute and late toxicities following either conformal RT (CRT) or IMRT for bladder cancer, and to correlate the toxicities to dose-volume parameters. Material and methods. The study included 116 consecutively treated patients with muscle-invasive bladder cancer who received either CRT (n = 66) or IMRT (n = 50) during 2007–2010. Acute side effects were retrospectively collected whereas late effects were assessed by a cross-sectional evaluation by telephone interview of 44 recurrence-free patients. Acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Event (CTCAE) version 3.0. Results. Acute diarrhoea grade ≥ 2 was more frequent in patients treated by CRT (56%) compared to IMRT (30%) (p = 0.008). Logistic regression analysis showed a correlation between acute diarrhoea and bowel cavity dose-volume parameters in the 10–50 Gy range. Severe late toxicity (grade ≥ 3) was recorded in 10% of the total cohort, with no statistical difference between the IMRT and CRT groups. Conclusion. Patients treated with IMRT for bladder cancer had significantly less acute diarrhoea compared to those treated with CRT, but there was no significant difference in late morbidity between the groups. The risk of acute diarrhoea was related to the volume of bowel irradiated.

A new fiducial marker for Image-guided radiotherapy of prostate cancer: Clinical experience

Background. A new fiducial marker for image guided radiotherapy (IGRT) based on a removable prostate stent made of Ni Ti has been developed during two previous clinical feasibility studies. The marker is currently being evaluated for IGRT treatment in a third clinical study. Method. The new marker is used to co-register MR and planning CT scans with high accuracy in the region around the prostate. The co-registered MR-CT volumes are used for delineation of GTV before planning. In each treatment session the IGRT system is used to position the patient before treatment. The IGRT system use a stereo pair of kV images matched to corresponding Digital Reconstructed Radiograms (DRR) from the planning CT scan. The match is done using mutual gray scale information. The pair of DRRs for positioning is created in the IGRT system with a threshold in the Look Up Table (LUT). The resulting match provides the necessary shift in couch coordinates to position the stent with an accuracy of 1-2 mm within the planned position. Results. At the present time 39 patients have received the new marker. Of the 39 one has migrated to the bladder. Deviations of more than 5 mm between CTV outlined on CT and MR are seen in several cases and in anterior-posterior (AP), left-right (LR) and cranial-caudal (CC) directions. Intra-fraction translation movements up to +/− 3 mm are seen as well. As the stent is also clearly visible on images taken with high voltage x-rays using electronic portal images devices (EPID), the positioning has been verified independently of the IGRT system. Discussion. The preliminary result of an on going clinical study of a Ni Ti prostate stent, potentially a new fiducial marker for image guided radiotherapy, looks promising. The risk of migration appears to be much lower compared to previous designs.

Salvage radiation therapy following radical prostatectomy. A national Danish study

Abstract Background: The purpose of this observational cohort study was to evaluate the outcome and prognostic factors following salvage radiotherapy (SRT) in a consecutive national cohort. Material and methods: Between 2006 and 2010, 259 patients received SRT in Denmark. Patient- and cancer-related characteristics were retrospectively retrieved from patient charts. The primary end point was biochemical progression-free survival (b-PFS). Results: At the end of follow-up, 51% of the patients displayed a prostate-specific antigen (PSA) level <0.1 ng/ml. The three-year b-PFS rate for the total cohort was 57.0%. Nearly half of the patients (44%) received androgen deprivation therapy (ADT) in combination with SRT. Positive surgical tumour margins (p = 0.025) and ADT (p = 0.001) were the only markers independently correlated with b-PFS. In patients who received SRT without ADT, both a pre-SRT PSA level ≤0.5 ng/ml (p = 0.003) and pathological tumour stage T1-T2 (p = 0.036) independently correlated with b-PFS. Moreover, a duration between radical prostatectomy (RP) and SRT ≤29 months (p = 0.035) independently correlated with b-PFS in patients treated with ADT in combination with RT. Conclusions: In patients treated for biochemical failure after RP, positive surgical tumour margins and PSA levels ≤0.5 ng/mL at the time of SRT were associated with a favourable outcome. Despite less favourable tumour characteristics, patients receiving SRT and ADT demonstrated improved b-PFS, and in particular, patients with PSA levels >0.2 ng/ml benefitted from additional ADT.

Clinical results from first use of prostate stent as fiducial for radiotherapy of prostate cancer

Abstract Purpose. A clinical feasibility study using a removable prostate stent as fiducial for image-guided radiotherapy (IGRT) of localized prostate cancer (PC). Material and methods. The study included patients with local or locally advanced PC. The clinical target volume (CTV) was outlined on magnetic resonance (MR) images co-registered to planning computer tomography (CT) images. Daily online IGRT was delivered using the stent as fiducial. Risk of migration was estimated using multiple MR. Acute urinary toxicity was scored using the international prostate symptom score (IPSS). Late gastro-intestinal (GI) and genito-urinary (GU) toxicity was scored using the Radio Therapy Oncology Group (RTOG) score, biochemical failure (BF) was defined as an elevation of prostate specific antigen (PSA) above nadir plus 2 ng/ml after radiotherapy. Results. One hundred men were enrolled in the study. Ninety completed radiotherapy with the stent as fiducial. No migration of the stent was seen, but three cases of dislocation of the stent to the bladder were observed. Acute urinary toxicity based on IPSS was comparable to toxicity in patients who had gold markers (GM) as fiducials. Removal of the stent was associated with a high frequency of urinary retention. Late GI and GU toxicity and BF were comparable to those of other studies, but longer observation time is needed. Conclusions. This study reports the first clinical results of using a prostate stent as fiducial. No migration of the stent observed. Dislocation of the stent to the urinary bladder was observed in three cases, requiring removal of the stent and insertion of a new fiducial. Acute toxicity during radiotherapy evaluated from IPSS was comparable to toxicity in patients with GM. Removal of the stent was associated with a high frequency of post procedural urinary retention. Late toxicity and BF were comparable to those of other studies, though longer observation time is needed.

Presurgical functional magnetic resonance imaging in patients with brain tumors

Background Clinical functional magnetic resonance imaging (fMRI) is still an upcoming diagnostic tool because it is time-consuming to perform the post-scan calculations and interpretations. A standardized and easily used method for the clinical assessment of fMRI scans could decrease the workload and make fMRI more attractive for clinical use. Purpose To evaluate a standardized clinical approach for distance measurement between benign brain tumors and eloquent cortex in terms of the ability to predict pre- and postoperative neurological deficits after intraoperative neuronavigation-assisted surgery. Material and Methods A retrospective study of 34 patients. The fMRI data were reanalyzed using a standardized distance measurement procedure combining data from both fMRI and three-dimensional T1 MRI scans. The pre- and postoperative neurological status of each patient was obtained from hospital records. Data analysis was performed using logistic regression analysis to determine whether the distance measured between the tumor margin and fMRI activity could serve as a predictor for neurological deficits. Results An odds ratio of 0.89 mm–1 (P = 0.03) was found between the risk of preoperative neurological motor deficits and the tumor-fMRI distance. An odds ratio of 0.82 mm–1 (P = 0.04) was found between the risk of additional postoperative neurological motor deficits and the tumor-fMRI distance. The tumor was radically removed in 10 cases; five patients experienced additional postoperative motor deficits (tumor-fMRI distance <18 mm) and five did not (tumor-fMRI distance >18 mm) (P = 0.008). Conclusion This study indicates that the distance measured between the tumor margin and fMRI activation could serve as a valuable predictor of neurological motor deficits.