BackgroundIntra-arterial radioembolization with yttrium-90 microspheres ( 90Y-RE) is an increasingly used therapy for patients with unresectable liver malignancies. Over the last decade, radioactive holmium-166 poly(L-lactic acid) microspheres ( 166Ho-PLLA-MS) have been developed as a possible alternative to 90Y-RE. Next to high-energy beta-radiation, 166Ho also emits gamma-radiation, which allows for imaging by gamma scintigraphy. In addition, Ho is a highly paramagnetic element and can therefore be visualized by MRI. These imaging modalities are useful for assessment of the biodistribution, and allow dosimetry through quantitative analysis of the scintigraphic and MR images. Previous studies have demonstrated the safety of 166Ho-PLLA-MS radioembolization ( 166Ho-RE) in animals. The aim of this phase I trial is to assess the safety and toxicity profile of 166Ho-RE in patients with liver metastases.MethodsThe HEPAR study (Holmium Embolization Particles for Arterial Radiotherapy) is a non-randomized, open label, safety study. We aim to include 15 to 24 patients with liver metastases of any origin, who have chemotherapy-refractory disease and who are not amenable to surgical resection. Prior to treatment, in addition to the standard technetium-99m labelled macroaggregated albumin ( 99mTc-MAA) dose, a low radioactive safety dose of 60-mg 166Ho-PLLA-MS will be administered. Patients are treated in 4 cohorts of 3-6 patients, according to a standard dose escalation protocol (20 Gy, 40 Gy, 60 Gy, and 80 Gy, respectively). The primary objective will be to establish the maximum tolerated radiation dose of 166Ho-PLLA-MS. Secondary objectives are to assess tumour response, biodistribution, performance status, quality of life, and to compare the 166Ho-PLLA-MS safety dose and the 99mTc-MAA dose distributions with respect to the ability to accurately predict microsphere distribution.DiscussionThis will be the first clinical study on 166Ho-RE. Based on preclinical studies, it is expected that 166Ho-RE has a safety and toxicity profile comparable to that of 90Y-RE. The biochemical and radionuclide characteristics of 166Ho-PLLA-MS that enable accurate dosimetry calculations and biodistribution assessment may however improve the overall safety of the procedure.Trial registrationClinicalTrials.gov NCT01031784
We aimed to assess the interobserver agreement of interim PET (I-PET) and end-of-treatment PET (EoT-PET) using the Deauville score (DS) in first-line diffuse large B-cell lymphoma (DLBCL) patients. I-PET and EoT-PET scans of DLBCL patients were performed in the HOVON84 study (2007-2012), an international multicenter randomized controlled trial. Patients received R-CHOP14 and were randomized to receive rituximab intensification in the first 4 cycles or not. I-PET was performed after 4 cycles (for observational purposes), and EoT-PET after 6 or 8 cycles. Two independent central reviewers retrospectively scored all scans according to the DS system, masked to clinical outcomes. Results were dichotomized as negative (DS of 1-3) or positive (DS of 4-5). Besides percentage overall agreement (OA), we calculated agreement for positive and negative scores, expressed as positive agreement (PA) and negative agreement (NA), respectively. 465 I-PET and 457 EoT-PET scans were centrally reviewed; baselineF-FDG PET or PET/CT was available in 75%-77%, and CT in the remaining cases. Percentage OA for I-PET and EoT-PET were 87.7% and 91.7% ( = 0.049), with NA of 92.0% and 95.0% ( = 0.091), and PA of 73.7% and 76.3% ( = 0.656), respectively. Interobserver agreement using DS in DLBCL patients in I-PET and EoT-PET yields high OA and NA. The lower PA suggests that EoT-PET/CT treatment evaluation in daily practice and I-PET-adapted trials may benefit from dual reads and central review, respectively.
Treatment of oncologic disease has improved significantly in the last decades and in the future a vast majority of cancer types will continue to increase worldwide. As a result, many patients are confronted with primary liver cancers or metastatic liver disease. Surgery in liver malignancies has steeply improved and curative resections are applicable in wider settings, leading to a prolonged survival. Simultaneously, radiofrequency ablation (RFA) and liver transplantation (LTx) have been applied more commonly in oncologic settings with improving results. To minimize adverse events in treatments of liver malignancies, locoregional minimal invasive treatments have made their appearance in this field, in which radioembolization (RE) has shown promising results in recent years with few adverse events and high response rates. We discuss several other applications of RE for oncologic patients, other than its use in the palliative setting, whether or not combined with other treatments. This review is focused on the role of RE in acquiring patient eligibility for radical treatments, like surgery, RFA, and LTx. Inducing significant tumor reduction can downstage patients for resection or, through attaining stable disease, patients can stay on the LTx waiting list. Hereby, RE could make a difference between curative of palliative intent in oncologic patient management. Prior to surgery, the future remnant liver volume might be inadequate in some patients. In these patients, forming an adequate liver reserve through RE leads to prolonged survival without risking post-operative liver failure and minimizing tumor progression while inducing hypertrophy. In order to optimize results, developments in procedures surrounding RE are equally important. Predicting the remaining liver function after radical treatment and finding the right balance between maximum tumor irradiation and minimizing the chance of inducing radiation-related complications are still challenges.
Patients with MYC-rearrangement positive large B-cell lymphoma (MYC+ LBCL) have an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) as compared to patients without MYC rearrangement. Although intensive chemotherapy regimens yield higher remission rates, toxicity remains a concern. Lenalidomide is an oral immunomodulatory drug which downregulates MYC and its target genes thereby providing support using lenalidomide as additional therapeutic option for MYC+ LBCL. A phase II trial was conducted evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients identified through a nationwide MYC-FISH screening program. The primary endpoint was complete metabolic response (CMR) on centrally reviewed 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computer tomography (CT)-scan at end-of-treatment. Secondary endpoints were overall survival (OS), disease-free survival (DFS) and event-free survival (EFS). Eighty-two patients with stage II-IV MYC+ LBCL were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 25.4 months, 2-year estimates (95% CI) for OS, DFS, EFS were 73% (62-82%), 75% (63-84%) and 63% (52-73%) respectively. In this prospective trial for newly diagnosed MYC+ LBCL patients, we found that administering R2CHOP was safe, and yields comparable CMR and survival rates as in studies applying more intensive chemotherapy regimens. Hence, these findings offer new prospects for MYC+ LBCL patients and warrant comparison in prospective randomized clinical trials. This trial was registered at www.clinicaltrialsregister.eu (#2014-002654-39).
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