Maurice A. A. J. van den Bosch

Effectiveness of Reirradiation for Painful Bone Metastases: A Systematic Review and Meta-Analysis

PURPOSE Reirradiation of painful bone metastases in nonresponders or patients with recurrent pain after initial response is performed in up to 42% of patients initially treated with radiotherapy. Literature on the effect of reirradiation for pain control in those patients is scarce. In this systematic review and meta-analysis, we quantify the effectiveness of reirradiation for achieving pain control in patients with painful bone metastases. METHODS AND MATERIALS A free text search was performed to identify eligible studies using the MEDLINE, EMBASE, and the Cochrane Collaboration library electronic databases. After study selection and quality assessment, a pooled estimate was calculated for overall pain response for reirradiation of metastatic bone pain. RESULTS Our literature search identified 707 titles, of which 10 articles were selected for systematic review and seven entered the meta-analysis. Overall study quality was mediocre. Of the 2,694 patients initially treated for metastatic bone pain, 527 (20%) patients underwent reirradiation. Overall, a pain response after reirradiation was achieved in 58% of patients (pooled overall response rate 0.58, 95% confidence interval = 0.49-0.67). There was a substantial between-study heterogeneity (I² = 63.3%, p = 0.01) because of clinical and methodological differences between studies. CONCLUSIONS Reirradiation of painful bone metastases is effective in terms of pain relief for a small majority of patients; approximately 40% of patients do not benefit from reirradiation. Although the validity of results is limited, this meta-analysis provides a comprehensive overview and the most quantitative estimate of reirradiation effectiveness to date.

Preoperative Imaging of Colorectal Liver Metastases After Neoadjuvant Chemotherapy: A Meta-Analysis

BackgroundChemotherapy treatment induces parenchymal changes that potentially affect imaging of CRLM. The purpose of this meta-analysis was to provide values of diagnostic performance of magnetic resonance imaging (MRI), computed tomography (CT), fluorodeoxyglucose positron emission tomography (FDG-PET), and FDG-PET/CT for preoperative detection of colorectal liver metastases (CRLM) in patients treated with neoadjuvant chemotherapy.MethodsA comprehensive search was performed for original articles published from inception to 2011 assessing diagnostic performance of MRI, CT, FDG-PET, or FDG-PET/CT for preoperative evaluation of CRLM following chemotherapy. Intraoperative findings and/or histology were used as reference standard. For each imaging modality we calculated pooled sensitivities for patients who received neoadjuvant chemotherapy as well as for chemonaive patients, defined as number of malignant lesions detected divided by number of malignant lesions as confirmed by the reference standard.ResultsA total of 11 papers, comprising 223 patients with 906 lesions, were included. Substantial variation in study design, patient characteristics, imaging features, and reference tests was observed. Pooled sensitivity estimates of MRI, CT, FDG-PET, and FDG-PET/CT were 85.7% (69.7–94.0%), 69.9% (65.6–73.9%), 54.5% (46.7–62.1%), and 51.7% (37.8–65.4%), respectively. In chemonaive patients, sensitivity rates were 80.5% (67.0–89.4%) for CT, 81.3% (64.1–91.4%) for FDG-PET, and 71.0% (64.3–76.9%) for FDG-PET/CT. Specificity could not be calculated because of non-reporting of “true negative lesions.”ConclusionIn the neoadjuvant setting, MRI appears to be the most appropriate imaging modality for preoperative assessment of patients with CRLM. CT is the second-best diagnostic modality and should be used in the absence of MRI. Diagnostic accuracy of FDG-PET and PET-CT is strongly affected by chemotherapy.

99mTc-Macroaggregated Albumin Poorly Predicts the Intrahepatic Distribution of 90Y Resin Microspheres in Hepatic Radioembolization

In hepatic 90Y radioembolization, pretreatment 99mTc-macroaggregated albumin (99mTc-MAA) nuclear imaging is used for lung shunt analysis, evaluation of extrahepatic deposition, and sometimes for treatment planning, using a partition model. A high level of agreement between pretreatment 99mTc-MAA distribution and final 90Y-microsphere distribution is assumed. The aim of this study was to investigate the value of pretreatment 99mTc-MAA SPECT to predict intrahepatic posttreatment 90Y-microsphere distribution. Methods: Volumes of interest (VOIs) were delineated on pretreatment contrast-enhanced CT or MR images according to Couinaud liver segmentation. All VOIs were registered to the 99mTc-MAA SPECT and 90Y SPECT images. The 99mTc-MAA SPECT and 90Y SPECT activity counts were normalized to the total administered activity of 90Y. For each VOI, this practice resulted in a predictive amount of 90Y (MBq/cm3) based on 99mTc-MAA SPECT in comparison with an actual amount of 90Y based on 90Y SPECT. Bland–Altman analysis was used to investigate the agreement of the activity distribution between 99mTc-MAA SPECT and 90Y SPECT. Results: A total of 39 procedures (225 VOIs) in 31 patients were included for analysis. The overall mean difference between pretreatment and posttreatment distribution of activity concentration for all segments was −0.022 MBq/cm3 with 95% limits of agreement of −0.581 to 0.537 MBq/cm3 (−28.9 to 26.7 Gy absorbed dose). A difference of >10%, >20%, and >30% of the mean activity per milliliter was found in, respectively, 153 (68%), 97 (43%), and 72 (32%) of the 225 segments. In every 99mTc-MAA procedure, at least 1 segment showed an under- or overestimation of >10%. The position of the catheter tip during administrations, as well as the tumor load of the liver segments, significantly influenced the disagreement. Conclusion: In current clinical practice, 99mTc-MAA distribution does not accurately predict final 90Y activity distribution. Awareness of the importance of catheter positioning and adherence to specific recommendations may lead to optimization of individualized treatment planning based on pretreatment imaging.

Quantitative Comparison of PET and Bremsstrahlung SPECT for Imaging the In Vivo Yttrium-90 Microsphere Distribution after Liver Radioembolization

Background After yttrium-90 (90Y) microsphere radioembolization (RE), evaluation of extrahepatic activity and liver dosimetry is typically performed on 90Y Bremsstrahlung SPECT images. Since these images demonstrate a low quantitative accuracy, 90Y PET has been suggested as an alternative. The aim of this study is to quantitatively compare SPECT and state-of-the-art PET on the ability to detect small accumulations of 90Y and on the accuracy of liver dosimetry. Methodology/Principal Findings SPECT/CT and PET/CT phantom data were acquired using several acquisition and reconstruction protocols, including resolution recovery and Time-Of-Flight (TOF) PET. Image contrast and noise were compared using a torso-shaped phantom containing six hot spheres of various sizes. The ability to detect extra- and intrahepatic accumulations of activity was tested by quantitative evaluation of the visibility and unique detectability of the phantom hot spheres. Image-based dose estimates of the phantom were compared to the true dose. For clinical illustration, the SPECT and PET-based estimated liver dose distributions of five RE patients were compared. At equal noise level, PET showed higher contrast recovery coefficients than SPECT. The highest contrast recovery coefficients were obtained with TOF PET reconstruction including resolution recovery. All six spheres were consistently visible on SPECT and PET images, but PET was able to uniquely detect smaller spheres than SPECT. TOF PET-based estimates of the dose in the phantom spheres were more accurate than SPECT-based dose estimates, with underestimations ranging from 45% (10-mm sphere) to 11% (37-mm sphere) for PET, and 75% to 58% for SPECT, respectively. The differences between TOF PET and SPECT dose-estimates were supported by the patient data. Conclusions/Significance In this study we quantitatively demonstrated that the image quality of state-of-the-art PET is superior over Bremsstrahlung SPECT for the assessment of the 90Y microsphere distribution after radioembolization.

Feasibility of 7 Tesla breast magnetic resonance imaging determination of intrinsic sensitivity and high-resolution magnetic resonance imaging, diffusion-weighted imaging, and 1H-magnetic resonance spectroscopy of breast cancer patients receiving neoadjuvant therapy

Objectives:To evaluate the feasibility of 7T breast magnetic resonance imaging (MRI) by determining the intrinsic sensitivity gain compared with 3T in healthy volunteers and to explore clinical application of 7T MRI in breast cancer patients receiving neoadjuvant chemotherapy (NAC). Materials and Methods:In 5 volunteers, the signal-to-noise ratio (SNR) was determined on proton density MRI at 3T using a conventional 4-channel bilateral breast coil and at 7T using a dedicated 2-channel unilateral breast coil, both obtained at identical scan parameters. Subsequently, consecutive breast cancer patients on NAC were included. The 7T breast MRI protocol consisted of diffusion-weighted imaging, 3D high-resolution (450 &mgr;m isotropic) T1-weighted fat-suppressed gradient-echo sequences and quantified single voxel 1H-magnetic resonance spectroscopy. Morphology was scored according to the MRI Breast Imaging-Reporting and Data System (BI-RADS)-lexicon, and the images were compared with 3T and histopathologic findings. Image quality was evaluated using a 5-point scale. Results:A 5.7-fold higher SNR was measured at 7T than at 3T, which reflects the advantages of a higher field strength and the use of optimized radiofrequency coils. Three breast cancer patients were included and received a total of 13 7T MRI examinations. The image quality of the high-resolution examinations was at least satisfactory, and good to excellent in 9 of the 13 examinations performed. More anatomic detail was depicted at 7T than at 3T. In 1 case, a fat plane between the muscle and tumor was visible at 7T, but not at the clinically performed 3T examination, suggesting that there was no muscle invasion, which was confirmed by pathology. Changes in tumor apparent diffusion coefficient values could be monitored in 2 patients and were found to increase during NAC, consistent with published results from studies at lower field strengths. Apparent diffusion coefficient values increased respectively from 0.33 × 10−3 mm2/s to 1.78 × 10−3 mm2/s after NAC and from 1.20 × 10−3 mm2/s to 1.44 × 10−3 mm2/s during NAC. Choline concentrations as low as 0.77 mMol/kgwater could be detected. In 1 patient, choline levels showed an overall decrease from 4.2 mMol/kwwater to 2.6 mMol/kgwater after NAC and the tumor size decreased correspondingly from 3.9 × 4.1 × 5.6 cm3 to 2.0 × 2.7 × 2.4 cm3. All 7T MRI findings were consistent with pathology analysis. Conclusion:Dedicated 7T breast MRI is technically feasible, can provide more SNR than at 3T, and has diagnostic potential.

Catheter-Directed Embolectomy, Fragmentation, and Thrombolysis for the Treatment of Massive Pulmonary Embolism After Failure of Systemic Thrombolysis

PURPOSES The standard medical management for patients in extremis from massive pulmonary embolism (PE) is systemic thrombolysis, but the utility of this treatment relative to catheter-directed intervention (CDI) is unknown. We evaluated the effectiveness of CDI as part of a treatment algorithm for life-threatening PE. METHODS A retrospective review was performed on 70 consecutive patients with suspected acute PE over a 10-year period (from 1997 to 2006) who had been referred for pulmonary angiography and/or intervention. The criteria for study inclusion were patients who received CDI due to angiographically confirmed massive PE and hemodynamic shock (shock index, > or = 0.9). CDI involved suction embolectomy and fragmentation with or without catheter thrombolysis. RESULTS Twelve patients were treated with CDI. There were seven men and five women (mean age, 56 years; age range, 21 to 80 years). Seven patients (58%) were referred for CDI after failing systemic infusion with 100 mg of tissue plasminogen activator, and five patients (42%) had contraindications to systemic thrombolysis. Catheter-directed fragmentation and embolectomy were performed in all patients (100%). Additionally, catheter-guided thrombolysis was performed in eight patients (67%). Technical success was achieved in 12 of 12 cases (100%). There were no major procedural complications (0%). Significant hemodynamic improvement (shock index, < 0.9) was observed in 10 of 12 cases (83%). The remaining two patients (17%) died secondary to cardiac arrest within 24 h. Ten of 12 patients (83%) survived and remained stable until hospital discharge (mean duration, 20 days; range, 3 to 51 days). CONCLUSION In the setting of hemodynamic shock from massive PE, CDI is potentially a life-saving treatment for patients who have not responded to or cannot tolerate systemic thrombolysis.

MR-guided high-intensity focused ultrasound ablation of breast cancer with a dedicated breast platform.

Optimizing the treatment of breast cancer remains a major topic of interest. In current clinical practice, breast-conserving therapy is the standard of care for patients with localized breast cancer. Technological developments have fueled interest in less invasive breast cancer treatment. Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a completely noninvasive ablation technique. Focused beams of ultrasound are used for ablation of the target lesion without disrupting the skin and subcutaneous tissues in the beam path. MRI is an excellent imaging method for tumor targeting, treatment monitoring, and evaluation of treatment results. The combination of HIFU and MR imaging offers an opportunity for image-guided ablation of breast cancer. Previous studies of MR-HIFU in breast cancer patients reported a limited efficacy, which hampered the clinical translation of this technique. These prior studies were performed without an MR-HIFU system specifically developed for breast cancer treatment. In this article, a novel and dedicated MR-HIFU breast platform is presented. This system has been designed for safe and effective MR-HIFU ablation of breast cancer. Furthermore, both clinical and technical challenges are discussed, which have to be solved before MR-HIFU ablation of breast cancer can be implemented in routine clinical practice.

Quantitative diffusion weighted imaging for differentiation of benign and malignant breast lesions: The influence of the choice of b‐values

To evaluate the influence of the choice of different combinations of b‐values on the ADC and on the diagnostic performance of quantitative diffusion weighted imaging (DWI) in breast lesions.

Minimally Invasive Ablative Therapies for Invasive Breast Carcinomas: An Overview of Current Literature

BackgroundMinimally invasive treatment may be an alternative to breast-conserving surgery.MethodsA structured PubMed, Embase, Cochrane, and Web of Science search was performed. Endpoints studied were feasibility, completeness of ablation, timing of the sentinel node biopsy (SNB), imaging modalities, and treatment-related complications.ResultsA total of 24 articles were retrieved, and the level of evidence varied (2B-4). Mainly phase II studies with a treat-and-resect protocol were analyzed. Up to 100% completeness of ablation was reported for radiofrequency ablation (RFA), cryosurgery, and focused ultrasound (FUS). The oncologic results need further evaluation. Dynamic contrast enhanced MRI seems to be the best method for monitoring treatment response (77% sensitivity, 100% specificity). Ultrasound is suitable for guiding probes into the tumor. There is no consensus on the timing of the SNB.ConclusionsAll studies on minimally invasive ablative modalities published so far show that these techniques are feasible and safe. At this stage only T1 tumors should be ablated in a clinical trial setting; it is unclear which of the modalities is most suitable.

Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study

BACKGROUND The efficacy of radioembolisation for the treatment of liver tumours depends on the selective distribution of radioactive microspheres to tumorous tissue. The distribution of holmium-166 ((166)Ho) poly(L-lactic acid) microspheres can be visualised in vivo by both single-photon-emission CT (SPECT) and MRI. In this phase 1 clinical trial, we aimed to assess the safety and the maximum tolerated radiation dose (MTRD) of (166)Ho-radioembolisation in patients with liver metastases. METHODS Between Nov 30, 2009, and Sept 19, 2011, patients with unresectable, chemorefractory liver metastases were enrolled in the Holmium Embolization Particles for Arterial Radiotherapy (HEPAR) trial. Patients were treated with intra-arterial (166)Ho-radioembolisation in cohorts of three patients, with escalating aimed whole-liver absorbed doses of 20, 40, 60, and 80 Gy. Cohorts were extended to a maximum of six patients if dose-limiting toxicity occurred. Patients were assigned a dose in the order of study entry, with dose escalation until dose-limiting toxicity was encountered in at least two patients of a dose cohort. Clinical or laboratory toxicities were scored according to the National Cancer Institutes Common Terminology Criteria for Adverse Events version 3.0. The primary endpoint was the MTRD. Analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT01031784. FINDINGS 15 patients underwent (166)Ho-radioembolisation at doses of 20 Gy (n=6), 40 Gy (n=3), 60 Gy (n=3), and 80 Gy (n=3). Mean estimated whole-liver absorbed doses were 18 Gy (SD 2) for the 20 Gy cohort, 35 Gy (SD 1) for the 40 Gy cohort, 58 Gy (SD 3) for the 60 Gy cohort, and 73 Gy (SD 4) for the 80 Gy cohort. The 20 Gy cohort was extended to six patients because of the occurrence of dose-limiting toxicity in one patient (pulmonary embolism). In the 80 Gy cohort, dose-limiting toxicity occurred in two patients: grade 4 thrombocytopenia, grade 3 leucopenia, and grade 3 hypoalbuminaemia in one patient, and grade 3 abdominal pain in another patient. The MTRD was identified as 60 Gy. The most frequently encountered laboratory toxicities (including grade 1) were lymphocytopenia, hypoalbuminaemia, raised alkaline phosphatase, raised aspartate aminotransferase, and raised gamma-glutamyltransferase, which were all noted in 12 of 15 patients. Stable disease or partial response regarding target lesions was achieved in 14 of 15 patients (93%, 95% CI 70-99) at 6 weeks and nine of 14 patients (64%, 95% CI 39-84) at 12 weeks after radioembolisation. Compared with baseline, the average global health status and quality of life scale score at 6 weeks after treatment had decreased by 13 points (p=0·053) and by 14 points at 12 weeks (p=0·048). In all patients, technetium-99m ((99m)Tc)-macro-aggregated albumin SPECT, (166)Ho scout dose SPECT, and (166)Ho treatment dose SPECT showed similar patterns of the presence or absence of extrahepatic deposition of activity. INTERPRETATION (166)Ho-radioembolisation is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment. Clinical (166)Ho-radioembolisation should be done with an aimed whole-liver absorbed dose of 60 Gy.