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B Methods: b SAKK 38/19 (NCT04604067) is an ongoing exploratory multicohort phase II trial in patients (pts) with previously untreated DLBCL not otherwise specified (NOS). Recently, genetic subtypes of DLBCL that go beyond the cell-of-origin and have distinct biology, clinical characteristics and different likelihood of response to specific therapies have been identified. SAKK 38/19: ASSESSING A CTDNA AND PET-ORIENTED THERAPY IN PATIENTS WITH DLBCL. [Extracted from the article]

Presents the results of a study on epidermal growth factor receptor (EGFR)-targeted immunoliposomes (IL) with the potential to provide intracellular drug delivery to EGFR and EGFRvIII-overexpressing tumor cells. Details of the preparation of lipososomes; Background on the cell lines used in the study, including human glioblastoma U-87; Characteristics of the cytotoxicity of Il containing doxorubicin and vinorelbine against EGFR overexpressing cells.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The REMoDL-B phase III adaptive trial compared rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) versus R-CHOP + bortezomib (RB-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL), stratified by molecular subtype. Primary analysis at a median follow-up of 30 months found no effect of bortezomib on progression-free survival (PFS) or overall survival (OS). Retrospective analysis using a gene expression-based classifier identified a molecular high-grade (MHG) group with worse outcomes. We present an updated analysis for patients successfully classified by the gene expression profile (GEP). Eligible patients were age older than 18 years with untreated DLBCL, fit enough for full-dose chemotherapy, and with adequate biopsies for GEP. Of 1,077 patients registered, 801 were identified with Activated B-Cell (ABC), Germinal Center B-cell, or MHG lymphoma. At a median follow-up of 64 months, there was no overall benefit of bortezomib on PFS or OS (5-year PFS hazard ratio [HR], 0.81; P = .085; OS HR, 0.86; P = .32). However, improved PFS and OS were seen in ABC lymphomas after RB-CHOP: 5-year OS 67% with R-CHOP versus 80% with RB-CHOP (HR, 0.58; 95% CI, 0.35 to 0.95; P = .032). Five-year PFS was higher in MHG lymphomas: 29% versus 55% (HR, 0.46; 95% CI, 0.26 to 0.84). Patients with ABC and MHG DLBCL may benefit from the addition of bortezomib to R-CHOP in initial therapy.

Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12 months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR). We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox). The payload consists of doxorubicin, a standard drug for TNBC. In a first-in-human phase I trial in 26 patients with various advanced solid malignancies, anti-EGFR-ILs-dox has shown little toxicity and encouraging efficacy. In this single-arm phase II trial, we assessed the efficacy of anti-EGFR-ILs-dox as first-line therapy in patients with advanced, EGFR + TNBC. The primary endpoint was progression-free survival at 12 months (PFS12m). Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to progression (TTP), overall survival (OS) and adverse events (AEs). 48 patients received anti-EGFR-ILs-dox 50 mg/m 2 iv, on day one of a 28 days-cycle until progression. The Kaplan-Meier estimate for PFS12m was 13% (one-sided 90% CI 7%, 95% CI [5%, 25%]), median PFS was 3.5 months (95% CI 1.9, 5.4). The trial has not reached its primary endpoint. There were no new toxicity signals. Based on these results, anti-EGFR-ILs-dox should not be further developed for TNBC. It remains an open question whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting this receptor has already shown anticancer effects.Trial registration: This trial was registered at clinicaltrials.gov: NCT02833766. Registered 14/07/2016., (© 2023. The Author(s).)

Introduction: In the treatment of advanced Hodgkin lymphoma (aHL), based on guidelines a multitude of treatment options are available. The availability of PET-guided decision-making and new therapeutic agents increase the complexity of the decision-making process., Methods: Thirteen experts of Swiss university and cantonal hospitals in Switzerland were asked to describe their institutional decision-making practice in aHL. Variables influencing the decision-making process were identified, standardized, and converted into decision trees for analysis of consent and discrepancies. The algorithms of all participating experts were analyzed with the objective consensus methodology., Results: Four decision criteria (age, fertility preservation, fitness, and interim PET) and 12 unique treatment regimens were identified. Consensus for the treatment of aHL for young and fit, as well as for older patients without comorbidity, was found. Large heterogeneity was identified with use of a variety of different regimens for unfit patients with aHL and for young female patients with a desire of fertility preservation., Conclusions: Four major decision criteria were identified allowing the representation of expert's approach to first-line treatment of aHL. Among Swiss experts, consensus for a PET-guided curative treatment of aHL was identified. The use of a multitude of treatment regimens was observed for older and comorbid (unfit) aHL patients, highlighting the need for clinical trials and recommendations for this group of patients., (© 2022 S. Karger AG, Basel.)

Accurate estimation of the progression risk after first-line therapy represents an unmet clinical need in diffuse large B-cell lymphoma (DLBCL). Baseline (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) parameters, together with genetic analysis of lymphoma cells, could refine the prediction of treatment failure. We evaluated the combined impact of mutation profiling and baseline PET/CT functional parameters on the outcome of DLBCL patients treated with the R-CHOP14 regimen in the SAKK38/07 clinical trial (NCT00544219). The concomitant presence of mutated SOCS1 with wild-type CREBBP and EP300 defined a group of patients with a favorable prognosis and 2-year progression-free survival (PFS) of 100%. Using an unsupervised recursive partitioning approach, we generated a classification-tree algorithm that predicts treatment outcomes. Patients with elevated metabolic tumor volume (MTV) and high metabolic heterogeneity (MH) (15%) had the highest risk of relapse. Patients with low MTV and favorable mutational profile (9%) had the lowest risk, while the remaining patients constituted the intermediate-risk group (76%). The resulting model stratified patients among three groups with 2-year PFS of 100%, 82%, and 42%, respectively ( p < 0.001).

Functional parameters from positron emission tomography (PET) seem promising biomarkers in various lymphoma subtypes. This study investigated the prognostic value of PET radiomics in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP given either every 14 (testing set) or 21 days (validation set). Using the PyRadiomics Python package, 107 radiomics features were extracted from baseline PET scans of 133 patients enrolled in the Swiss Group for Clinical Cancer Research 38/07 prospective clinical trial (SAKK 38/07) [ClinicalTrial.gov identifier: NCT00544219]. The international prognostic indices, the main clinical parameters and standard PET metrics, together with 52 radiomics uncorrelated features (selected using the Spearman correlation test) were included in a least absolute shrinkage and selection operator (LASSO) Cox regression to assess their impact on progression-free (PFS), cause-specific (CSS), and overall survival (OS). A linear combination of the resulting parameters generated a prognostic radiomics score (RS) whose area under the curve (AUC) was calculated by receiver operating characteristic analysis. The RS efficacy was validated in an independent cohort of 107 DLBCL patients. LASSO Cox regression identified four radiomics features predicting PFS in SAKK 38/07. The derived RS showed a significant capability to foresee PFS in both testing (AUC, 0.709; p < 0.001) and validation (AUC, 0.706; p < 0.001) sets. RS was significantly associated also with CSS and OS in testing (CSS: AUC, 0.721; p < 0.001; OS: AUC, 0.740; p < 0.001) and validation (CSS: AUC, 0.763; p < 0.0001; OS: AUC, 0.703; p = 0.004) sets. The RS allowed risk classification of patients with significantly different PFS, CSS, and OS in both cohorts showing better predictive accuracy respect to clinical international indices. PET-derived radiomics may improve the prediction of outcome in DLBCL patients., (© 2022 John Wiley & Sons Ltd.)

Positron emission computed tomography (PET/CT) in patients with diffuse large B-cell lymphoma (DLBCL) enrolled in a prospective clinical trial were reviewed to test the impact of quantitative parameters from interim PET/CT scans on overall (OS) and progression-free (PFS) survival. We centrally reviewed baseline and interim PET/CT scans of 138 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone given every 14 days (R-CHOP14) in the SAKK38/07 trial (ClinicalTrial.gov identifier: NCT00544219). Cutoff values for maximum standardized uptake value (SUV max ), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and metabolic heterogeneity (MH) were defined by receiver operating characteristic analysis. Responses were scored using the Deauville scale (DS). Patients with DS 5 at interim PET/CT (defined by uptake >2 times higher than in normal liver) had worse PFS (P = 0.014) and OS (P < 0.0001). A SUV max reduction (Δ) greater than 66% was associated with longer PFS (P = 0.0027) and OS (P < 0.0001). Elevated SUV max , MTV, TLG, and MH at interim PET/CT also identified patients with poorer outcome. At multivariable analysis, ΔSUV max and baseline MTV appeared independent outcome predictors. A prognostic model integrating ΔSUV max and baseline MTV discriminated three risk groups with significantly (log-rank test for trend, P < 0.0001) different PFS and OS. Moreover, the integration of MH and clinical prognostic indices could further refine the prediction of OS. PET metrics-derived prognostic models perform better than the international indices alone. Integration of baseline and interim PET metrics identified poor-risk DLBCL patients who might benefit from alternative treatments., (© 2020 John Wiley & Sons Ltd.)

Gliomas are intrinsic brain tumours, which are classified by the World Health Organization (WHO) into different grades of malignancy, with glioblastoma being the most frequent and most malignant subtype (WHO grade IV). Mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes are frequent in lower (WHO II/III) grade tumours but typically absent in classical glioblastoma. IDH mutations are associated with a better prognosis compared with IDH wild-type tumours of the same WHO grade. Following detection of a tumour mass by imaging, maximum safe surgery as feasible is commonly performed to reduce mass effect and to obtain tissue allowing histopathological diagnosis and molecular assessment. Radiotherapy has been the mainstay in the treatment of diffuse gliomas for several decades. It provides improved local control, but is not curative. Furthermore, several randomised trials have shown that the addition of alkylating chemotherapy, either temozolomide or nitrosourea-based regimens, to radiotherapy results in prolonged survival. Tumour-treating fields (TTFields) have emerged as an additional treatment option in combination with maintenance temozolomide treatment for patients with newly diagnosed glioblastoma. Treatment at recurrence is less standardised and depends on the patient&rsquo;s performance status, symptom burden and prior treatments. Bevacizumab prolongs progression-free survival in newly diagnosed and recurrent glioblastoma, but does not impact overall survival. However, in Switzerland and some other countries, it is still considered a valuable treatment option to reduce clinical symptom burden. Given the generally poor outcome for these patients, various novel treatment approaches are currently being explored within clinical trials including immunotherapeutic strategies such as immune checkpoint inhibition and the brain-penetrant proteasome inhibitor marizomib.

Several functional parameters from baseline (18)F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography have been proposed as promising biomarkers of treatment efficacy in diffuse large B-cell lymphoma (DLBCL). We tested their ability to predict outcome in 2 cohorts of DLBCL patients receiving conventional immunochemotherapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone [R-CHOP] regimen), either every 14 (R-CHOP14) or 21 days (R-CHOP21). Baseline PET analysis was performed in 141 patients with DLBCL treated with R-CHOP14 in the prospective SAKK38/07 study (NCT00544219) of the Swiss Group for Clinical Cancer Research (testing set). Reproducibility was examined in a validation set of 113 patients treated with R-CHOP21. In the SAKK38/07 cohort, progression-free survival (PFS) at 5 years was 83% for patients with low metabolic tumor volume (MTV) and 59% for those with high MTV (hazard ratio [HR], 3.4; 95% confidence interval [CI], 1.6-7.0; P = .0005), whereas overall survival (OS) was 91% and 64%, respectively (HR, 4.4; 95% CI, 1.9-10; P = .0001). MTV was the most powerful predictor of outcome also in the validation set. Elevated metabolic heterogeneity (MH) significantly predicted poorer outcomes in the subgroups of patients with elevated MTV. A model integrating MTV and MH identified high-risk patients with shorter PFS (testing set: HR, 5.6; 95% CI, 1.8-17; P < .0001; validation set: HR, 5.6; 95% CI, 1.7-18; P = .0002) and shorter OS (testing set: HR, 9.5; 95% CI, 1.7-52; P < .0001; validation set: HR, 7.6; 95% CI, 2.0-28; P = .0003). This finding was confirmed by an unsupervised regression tree analysis indicating that prognostic models based on MTV and MH may allow early identification of refractory patients who might benefit from treatment intensification. This trial was registered at www.clinicaltrials.gov as #NCT00544219., (© 2020 by The American Society of Hematology.)

Background: The impact of HER2-targeted therapy alone followed by the addition of chemotherapy at disease progression (PD) versus upfront combination was investigated by the SAKK 22/99 trial. The aim of this exploratory analysis of the SAKK 22/99 trial was to characterize the specific subset of patients deriving long-term benefit from trastuzumab monotherapy alone and to identify potential predictive factors of long-term response., Methods: This is an unplanned post-hoc analysis of patients randomized to Arm A (trastuzumab monotherapy). Patients were divided in two groups: patients with durable clinical benefit from trastuzumab monotherapy and short-term responders without durable clinical benefit from trastuzumab monotherapy Univariate and multivariate analyses of clinical characteristics correlating with response duration was performed., Results: Eighty six patients were randomized in arm A, 24 patients (28%) were long-term responders and 62 (72%) were short-term responders with a 5y-overall survival (OS) of 54% (95% CI 31-72) and of 18% (95%CI 10-30), respectively. Absence of ER expression, absence of PgR expression and presence of visceral disease emerged as possible negative predictive factors for durable clinical benefit., Conclusion: Durable clinical benefit can be achieved with trastuzumab monotherapy in a subgroup of HER2-positive patients with advanced disease and it is predictive for longer OS. Further investigations of predictive biomarkers are necessary to better characterize this subgroup of patients and develop further de-escalating strategies., Trial Registration: NCT00004935 ; first posted 27.01.2003, retrospectively registered.