Data of previous trials with a similar setting are often available in the analysis of clinical trials. Several Bayesian methods have been proposed for including historical data as prior information ...in the analysis of the current trial, such as the (modified) power prior, the (robust) meta-analytic-predictive prior, the commensurate prior and methods proposed by Pocock and Murray et al. We compared these methods and illustrated their use in a practical setting, including an assessment of the comparability of the current and the historical data. The motivating data set consists of randomised controlled trials for acute myeloid leukaemia. A simulation study was used to compare the methods in terms of bias, precision, power and type I error rate. Methods that estimate parameters for the between-trial heterogeneity generally offer the best trade-off of power, precision and type I error, with the meta-analytic-predictive prior being the most promising method. The results show that it can be feasible to include historical data in the analysis of clinical trials, if an appropriate method is used to estimate the heterogeneity between trials, and the historical data satisfy criteria for comparability.
Abstract Adding hyperthermia to standard radiotherapy (RT + HT) improves treatment outcome for patients with locally advanced cervical cancer (LACC). We investigated the effect of hyperthermia dose ...on treatment outcome for patients with LACC treated with RT + HT. We collected treatment and outcome data of 420 patients with LACC treated with hyperthermia at our institute from 1990 to 2005. Univariate and multivariate analyses were performed on response rate, local control, disease-specific survival and toxicity for these patients to search for a thermal dose response relationship. Besides commonly identified prognostic factors in LACC like tumour stage, performance status, radiotherapy dose and tumour size, thermal parameters involving both temperature and duration of heating emerged as significant predictors of the various end-points. The more commonly used CEM43T90 (cumulative equivalent minutes of T90 above 43 °C) was less influential than TRISE (based on the average T50 increase and the duration of heating, normalised to the scheduled duration of treatment). CEM43T90 and TRISE measured intraluminally correlate significantly and independently with tumour control and survival. These findings stimulate further technological development and improvement of deep hyperthermia, as they strongly suggest that it might be worthwhile to increase the thermal dose for LACC, either by treatment optimisation or by prolonging the treatment time. These results also confirm the beneficial effects from hyperthermia as demonstrated in our earlier randomised trial, and justify applying radiotherapy and hyperthermia as treatment of choice for patients with advanced cervical cancer.
Venous thromboembolism is a common complication in patients with cancer, but only limited data are available in acute myeloid leukemia (AML). In a prospective study in a cohort of 272 adult patients ...(aged 18-65) and an independent validation cohort of 132 elderly adults (aged >60) with newly diagnosed AML, we assessed markers of disseminated intravascular coagulation (DIC) (fibrinogen, D-dimer, α-2-antiplasmin, antitrombin, prothrombin time, and platelet count) and the DIC score according the International Society of Thrombosis and Haemostasis and their associations with the occurrence of venous and arterial thrombosis during follow-up. The prevalence of thrombosis was 8.7% (4.7% venous, 4.0% arterial) in the younger adults over a median follow-up of 478 days and 10.4% (4.4% venous, 5.9% arterial) in elderly patients. Most thrombotic events (66%) occurred before the start of the second course of chemotherapy. The calculated DIC score significantly predicted venous and arterial thrombosis with a hazard ratio (HR) for a high DIC score (≥5) of 4.79 (1.71-13.45). These results were confirmed in the validation cohort of elderly patients with AML (HR 11.08 3.23-38.06). Among all DIC parameters, D-dimer levels are most predictive for thrombosis with an HR of 12.3 (3.39-42.64) in the first cohort and an HR of 7.82 (1.95-31.38) in validation cohort for a D-dimer >4 mg/L vs ≤4 mg/L. It is concluded that venous and arterial thrombosis may develop in ∼10% of AML patients treated with intensive chemotherapy, which to a large extent can be predicted by the presence of DIC at time of AML diagnosis.
•A high D-dimer level strongly predicts symptomatic venous and arterial thrombosis in newly diagnosed AML.•Thrombosis occurs in up to 10% of patients with newly diagnosed AML.
An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in ...this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).
Highlights • The age-standardized incidence rate (ASR) per 100,000 was 5.4 for MDS and 0.4 for CMML. • The ASR of MDS was almost 2-fold higher than in the Netherlands Cancer Registry (NCR). • Almost ...half of all cases were diagnosed without a bone marrow examination (BM). • The ASR in the MDS cohort with BM examinations was comparable with the NCR. • The majority of patients, either with or without BM examinations, received no therapy.
Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) ...after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM‐risk scores in patients receiving PTCY‐based GVHD prophylaxis, and subsequently developed and validated a novel PTCY‐specific NRM‐risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY‐based GVHD prophylaxis were included. The PTCY‐risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation‐comorbidity index (HCT‐CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2‐year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT‐CI, and integrated EBMT score was relatively poor for discriminating 2‐year NRM (c‐statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY‐risk score included 10 variables which were collapsed in 3 risk groups estimating 2‐year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c‐statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c‐statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM‐risk score for acute leukemia patients receiving PTCY that better predicted 2‐year NRM compared with existing models, which might be applicable to the specific toxicities of high‐dose cyclophosphamide.
Radiotherapy (RT) is the standard of care for most advanced head and neck squamous cell carcinoma (HNSCC) and results in an unfavorable 5-year overall survival of 40%. Despite strong biological ...rationale, combining RT with immune checkpoint inhibitors does not result in a survival benefit. Our hypothesis is that the combination of these individually effective treatments fails because of radiation-induced immunosuppression and lymphodepletion. By integrating modern radiobiology and innovative radiotherapy concepts, the patient's immune system could be maximally retained by (1) increasing the dose per fraction so that the total dose and number of fractions can be reduced (HYpofractionation), (2) redistributing the radiation dose towards a higher peak dose within the tumor center and a lowered elective lymphatic field dose (Dose-redistribution), and (3) using RAdiotherapy with protons instead of photons (HYDRA).
The primary aim of this multicenter study is to determine the safety of HYDRA proton- and photon radiotherapy by conducting two parallel phase I trials. Both HYDRA arms are randomized with the standard of care for longitudinal immune profiling. There will be a specific focus on actionable immune targets and their temporal patterns that can be tested in future hypofractionated immunoradiotherapy trials. The HYDRA dose prescriptions (in 20 fractions) are 40 Gy elective dose and 55 Gy simultaneous integrated boost on the clinical target volume with a 59 Gy focal boost on the tumor center. A total of 100 patients (25 per treatment group) will be recruited, and the final analysis will be performed one year after the last patient has been included.
In the context of HNSCC, hypofractionation has historically only been reserved for small tumors out of fear for late normal tissue toxicity. To date, hypofractionated radiotherapy may also be safe for larger tumors, as both the radiation dose and volume can be reduced by the combination of advanced imaging for better target definition, novel accelerated repopulation models and high-precision radiation treatment planning and dose delivery. HYDRA's expected immune-sparing effect may lead to improved outcomes by allowing for future effective combination treatment with immunotherapy.
The trial is registered at ClinicalTrials.gov; NCT05364411 (registered on May 6th, 2022).
To report response rate, pelvic tumor control, survival, and late toxicity after treatment with combined radiotherapy and hyperthermia (RHT) for patients with locally advanced cervical carcinoma ...(LACC) and compare the results with other published series.
From 1996 to 2005, a total of 378 patients with LACC (International Federation of Gynecology and Obstetrics Stage IB2-IVA) were treated with RHT. External beam radiotherapy (RT) was applied to 46-50.4 Gy and combined with brachytherapy. The hyperthermia (HT) was prescribed once weekly. Primary end points were complete response (CR) and local control. Secondary end points were overall survival, disease-specific survival, and late toxicity. Patient, tumor, and treatment characteristics predictive for the end points were identified in univariate and multivariate analyses.
Overall, a CR was achieved in 77% of patients. At 5 years, local control, disease-specific survival, and incidence of late toxicity Common Terminology Criteria for Adverse Events Grade 3 or higher were 53%, 47%, and 12%, respectively. In multivariate analysis, number of HT treatments emerged as a predictor of outcome in addition to commonly identified prognostic factors.
The CR, local control, and survival rates are similar to previously observed results of RHT in the randomized Dutch Deep Hyperthermia Trial. Reported treatment results for currently applied combined treatment modalities (i.e., RT with chemotherapy and/or HT) do not permit definite conclusions about which combination is superior. The present results confirm previously shown beneficial effects from adding HT to RT and justify the application of RHT as first-line treatment in patients with LACC as an alternative to chemoradiation.
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