John M.H. de Klerk

Newly Diagnosed Lymphoma: Initial Results With Whole-Body T1-Weighted, STIR, and Diffusion-Weighted MRI Compared With 18F-FDG PET/CT

OBJECTIVE The purpose of this study was to compare whole-body MRI including diffusion-weighted imaging (DWI) with (18)F-FDG PET/CT in the staging of newly diagnosed lymphoma. SUBJECTS AND METHODS Twenty-two consecutively registered patients with newly diagnosed lymphoma prospectively underwent whole-body MRI (22 with T1-weighted, STIR, and DWI sequences and 21 with T1-weighted and STIR sequences but not DWI) and FDG PET/CT. Whole-body MRI-DWI was independently evaluated by two blinded observers. Interobserver agreement was assessed, and whole-body MRI-DWI was compared with FDG PET/CT. RESULTS The kappa values for interobserver agreement on whole-body MRI-DWI for all nodal regions together and for all extranodal regions together were 0.676 and 0.452. The kappa values for agreement between whole-body MRI-DWI and FDG PET/CT for all nodal regions together and for all extranodal regions together were 0.597 and 0.507. Ann Arbor stage according to whole-body MRI-DWI findings was concordant with that of FDG PET/CT findings in 77% (17/22) of patients. Understaging and overstaging relative to the findings with FDG PET/CT occurred in 0% (0/22) and 23% (5/22) of cases. In the care of 9% (2/22) of patients, overstaging with whole-body MRI-DWI relative to staging with FDG PET/CT would have had therapeutic consequences. CONCLUSION Our early results indicate that overall interobserver agreement on whole-body MRI-DWI findings is moderate to good. Overall agreement between whole-body MRI-DWI and FDG PET/CT is moderate. In the care of patients with newly diagnosed lymphoma, staging with whole-body MRI-DWI does not result in underestimation of stage relative to the results with FDG PET/CT. In a minority of patients, reliance on whole-body MRI-DWI leads to clinically important overstaging relative to the results with FDG PET/CT. FDG PET/CT remains the reference standard for lymphoma staging until larger-scale studies show that use of whole-body MRI-DWI results in correct staging in this minority of cases.

Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer

Rhenium-186 hydroxyethylidene diphosphonate (186Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using 186Re-HEDP Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the 186Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq 186Re-HEDP showed grade 3 toxicity (thrombocytes 25–50 × 109/1), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% ± 10% IUA; range: 11%–44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of 186Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of 186Re-HEDP has been initiated.

CT and 18F-FDG PET for noninvasive detection of splenic involvement in patients with malignant lymphoma.

OBJECTIVE The purpose of this study was to determine the sensitivity and specificity of (18)F-FDG PET, CT, and combined PET/CT in the detection of splenic involvement at initial staging of lymphoma. MATERIALS AND METHODS A retrospective longitudinal analysis was performed on the records of 111 patients with proven lymphoma who had undergone PET and CT before and after treatment. CT scans were evaluated independently by two radiologists, and PET scans by two nuclear medicine physicians. Abnormal CT findings were defined as low-attenuation nodules or a splenic index greater than 725 cm(3) (> 2 SDs above the mean in 100 controls). An abnormal PET finding was defined as splenic uptake greater than hepatic uptake. True splenic involvement was defined retrospectively on the basis of the treatment response assessed with criteria revised in the International Harmonization Project on lymphoma. Observer agreement and sensitivity and specificity values were calculated. RESULTS Observer agreement for CT splenic index and PET findings was good. For initial splenic staging, the sensitivity and specificity of CT, PET, and PET/CT were 91% and 96%, 75% and 99%, and 100% and 95%. CONCLUSION For initial staging of splenic involvement in malignant lymphoma, the sensitivity and specificity of PET/CT can reach 100% and 95%. The sensitivity of the combined approach is higher than that of either technique alone.

Bone marrow 18F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography cannot replace bone marrow biopsy in diffuse large B-cell lymphoma

This study aimed to investigate whether visual and quantitative 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography/computed tomography (FDG‐PET/CT)‐based bone marrow assessment can replace blind bone marrow biopsy (BMB) in newly diagnosed diffuse large B‐cell lymphoma (DLBCL). This retrospective study included 78 patients with newly diagnosed DLBCL who had undergone both FDG‐PET/CT and BMB. FDG‐PET/CT images were visually evaluated for bone marrow involvement. Patient‐based sensitivity of visual FDG‐PET/CT assessment was calculated using BMB as the reference standard. Metabolically active volume, maximum standardized uptake value, 3D partial volume corrected mean standardized uptake value, and 3D partial volume corrected mean metabolic volume product (cMVPmean) of FDG‐avid bone marrow lesions were measured. Cox regression analysis was used to determine the influence of (potential) prognostic factors (BMB status, visual [dichotomous] FDG‐PET/CT bone marrow status, metabolically active volume, maximum standardized uptake value, 3D partial volume corrected mean standardized uptake value, 3D partial volume corrected mean metabolic volume product, and International Prognostic Index score) on progression‐free survival and overall survival. FDG‐PET/CT detected bone marrow involvement in 34 (43.6%) cases and BMB in 16 (20.5%) of 78 cases, of whom 11 were also detected by FDG‐PET/CT, resulting in a patient‐based sensitivity of 68.8% (95% confidence interval = 44.2%–86.1%) for FDG‐PET/CT. In the multivariate Cox proportional hazards model, only BMB status was an independent predictive factor of progression‐free survival (P = 0.016) and overall survival (P = 0.004). In conclusion, FDG‐PET/CT misses bone marrow involvement that has been detected by BMB in a non‐negligible proportion of patients. Furthermore, both visual and quantitative FDG‐PET/CT‐based bone marrow assessments are prognostically inferior to BMB. Therefore, FDG‐PET/CT cannot replace BMB in newly diagnosed DLBCL. Am. J. Hematol. 89:726–731, 2014.

Targeting of liver tumour in rats by selective delivery of holmium-166 loaded microspheres: a biodistribution study

Abstract. Intra-arterial administration of beta-emitting particles that become trapped in the vascular bed of a tumour and remain there while delivering high doses, represents a unique approach in the treatment of both primary and metastatic liver tumours. Studies on selective internal radiation therapy of colorectal liver metastases using yttrium-90 glass microspheres have shown encouraging results. This study describes the biodistribution of 40-µm poly lactic acid microspheres loaded with radioactive holmium-166, after intra-arterial administration into the hepatic artery of rats with implanted liver tumours. Radioactivity measurements showed >95% retention of injected activity in the liver and its resident tumour. The average activity detected in other tissues was ≤0.1%ID/g, with incidental exceptions in the lungs and stomach. Very little 166Ho activity was detected in kidneys (<0.1%ID/g), thereby indicating the stability of the microspheres in vivo. Tumour targeting was very effective, with a mean tumour to liver ratio of 6.1±2.9 for rats with tumour (n=15) versus 0.7±0.5 for control rats (n=6; P<0.001). These ratios were not significantly affected by the use of adrenaline. Histological analysis showed that five times as many large (>10) and medium-sized (4–9) clusters of microspheres were present within tumour and peritumoural tissue, compared with normal liver. Single microspheres were equally dispersed throughout the tumour, as well as normal liver parenchyma.

Clinical applications of 188Re-labelled radiopharmaceuticals for radionuclide therapy.

188Re is a radionuclide in which there is widespread interest for therapeutic purposes because of its favourable physical characteristics. Moreover, it can be eluted from an on-site installable 188W/188Re generator, which has a useful shelf-life of several months. Most of the clinical experiences gained with 188Re concern the use of 188Re-1,1-hydroxyethylidenediphosphonate (188Re-HEDP) for bone pain palliation in patients suffering prostate cancer. The maximum tolerated activity was 3.3 GBq 188Re-HEDP and if the platelet count exceeded 200×109 l−1, the administration of 4.4 GBq appeared safe. Evidence for repeated administrations of 188Re-HEDP rather than single injections was established. In general, pain palliation occurs in 60–92% of patients with only moderate transient toxicity, mainly related to changes in blood counts. Also in haematology, radioimmunotherapy by means of 188Re might play a role by selectively targeting the bone marrow in patients undergoing conditioning prior to haematopoetic stem cell transplantation. The feasibility of such an approach was proven using a 188Re-labelled monoclonal antibody directed toward the CD66-antigen. More recently, encouraging safety data on locoregional treatment of primary liver tumours using 188Re-labelled lipiodol were reported. The normal organs at greatest risk for toxicity are the normal liver and the lungs. About 50% of the patients reported mild and transient side effects, mainly consisting of low grade fever, right hypochondrial discomfort or aggravation of pre-existing liver impairment. Besides the applications in oncology 188Re-based therapies have also been pioneered for benign condition such as prevention of re-stenosis following angioplasty and for radiosynovectomy in cases of refractory arthritis.

Standardized radioiodine therapy in Graves' disease: the persistent effect of thyroid weight and radioiodine uptake on outcome

Abstract. Objective. To assess the incidence of hypothyroidism, euthyroidism, and recurrent hyperthyroidism following a standard dose of Na131I (3.7 MBq or 100 μCi) per g thyroid tissue, adjusted for radioiodine tracer uptake.

Whole-body MRI, including diffusion-weighted imaging, for staging lymphoma: Comparison with CT in a prospective multicenter study

To compare whole‐body magnetic resonance imaging (MRI), including diffusion‐weighted imaging (DWI), to computed tomography (CT) for staging newly diagnosed lymphoma.

186Re-HEDP for metastatic bone pain in breast cancer patients

Two-thirds of patients with metastatic cancer suffer from pain. Pain originating from skeletal metastases is the most common form of cancer-related pain. Bone pain, often exacerbated by pressure or movement, limits the patient’s autonomy and social life. Pain palliation with bone-seeking radiopharmaceuticals has proven to be an effective treatment modality in patients with metastatic bone pain. These bone-seeking radiopharmaceuticals are extremely powerful in treating scattered painful bone metastases, for which external beam radiotherapy is impossible because of the large field of irradiation. 186Re-hydroxyethylidene diphosphonate (HEDP) is a potentially useful radiopharmaceutical for this purpose, having numerous advantageous characteristics. Bone marrow toxicity is limited and reversible, which makes repetitive treatment safe. Studies have shown encouraging clinical results of palliative therapy using 186Re-HEDP, with an overall response rate of ca. 70% in painful bone metastases. It is effective for fast palliation of painful bone metastases from various tumours and the effect tends to last longer if patients are treated early in the course of their disease. 186Re-HEDP is at least as effective in breast cancer patients with painful bone metastases as in patients with metastatic prostate cancer. It is to be preferred to radiopharmaceuticals with a long physical half-life in this group of patients, who tend to have more extensive haematological toxicity since they have frequently been pretreated with bone marrow suppressive chemotherapy. This systemic form of radionuclide therapy is simple to administer and complements other treatment options. It has been associated with marked pain reduction, improved mobility in many patients, reduced dependence on analgesics, and improved performance status and quality of life.

Radiopharmaceuticals for Palliation of Bone Pain in Patients with Castration-resistant Prostate Cancer Metastatic to Bone: A Systematic Review

CONTEXT The majority of patients with castration-resistant prostate cancer develop bone metastatic disease. It is often challenging to optimally palliate malignant bone pain. In case of multifocal pain due to diffuse osteoblastic metastases, treatment with bone-seeking radiopharmaceuticals can be considered. OBJECTIVE This systematic review evaluates the efficacy of different bone-seeking radiopharmaceuticals for palliation of malignant bone pain from prostate cancer. EVIDENCE ACQUISITION The PubMed (Medline) and Embase databases were searched for publications on 89-strontium-chloride ((89)Sr), 153-samarium-EDTMP ((153)Sm), 186-rhenium-HEDP ((186)Re), 188-rhenium-HEDP ((188)Re), and 223-radium-chloride ((223)Ra). Randomised controlled trials and prospective cohort studies were included. Metastatic bone pain had to be registered as outcome measure for prostate cancer patients separately. EVIDENCE SYNTHESIS This review included 36 articles of which 13 randomised trials and 23 prospective studies. Of all trials, 10 studies used (89)Sr, 7 (153)Sm, 12 (186)Re, 2 (188)Re, and 2 (223)Ra; three reported on a combination of different radionuclides. Only a few trials contained a blinding procedure and several studies contained incomplete follow-up or lack of intention-to-treat analysis. It was not possible to calculate a pooled estimate of pain response to treatment with any of the radionuclides because different definitions of pain response were used. CONCLUSIONS Overall, pain response percentages greater than 50-60% were seen with each radionuclide. Haematological toxicity was reported in 26 of the 36 studies and more than half of these trials stated no grade 3/4 leukopenia or thrombocytopenia occurred. PATIENT SUMMARY In this report we reviewed the efficacy of bone-seeking radionuclides for treating bone pain from metastatic prostate cancer. Overall, treatment with bone-seeking radionuclides resulted in pain responses greater than 50-60%.