Abstract
Background
Trials in the USA and Europe have convincingly demonstrated the efficacy of screening by low-dose computed tomography (LDCT) as a means to lower lung cancer mortality, but also ...document potential harms related to radiation, psychosocial stress, and invasive examinations triggered by false-positive screening tests and overdiagnosis. To ensure that benefits (lung cancer deaths averted; life years gained) outweigh the risk of harm, lung cancer screening should be targeted exclusively to individuals who have an elevated risk of lung cancer, plus sufficient residual life expectancy.
Methods and Conclusions
Overall, randomized screening trials show an approximate 20 % reduction in lung cancer mortality by LDCT screening. In view of declining residual life expectancy, especially among continuing long-term smokers, risk of being over-diagnosed is likely to increase rapidly above the age of 75. In contrast, before age 50, the incidence of LC may be generally too low for screening to provide a positive balance of benefits to harms and financial costs. Concise criteria as used in the NLST or NELSON trials may provide a basic guideline for screening eligibility. An alternative would be the use of risk prediction models based on smoking history, sex, and age as a continuous risk factor. Compared to concise criteria, such models have been found to identify a 10 % to 20 % larger number of LC patients for an equivalent number of individuals to be screened, and additionally may help provide security that screening participants will all have a high-enough LC risk to balance out harm potentially caused by radiation or false-positive screening tests.
Key Points:
LDCT screening can significantly reduce lung cancer mortality
Screening until the age of 80 was shown to be efficient in terms of cancer deaths averted; in terms of LYG relative to overdiagnosis, stopping at a younger age (e. g. 75) may have greater efficiency
Risk models may improve the overall net benefit of lung cancer screening
Citation Format
Kaaks R, Delorme S. Lung Cancer Screening by Low-Dose Computed Tomography – Part 1: Expected Benefits, Possible Harms, and Criteria for Eligibility and Population Targeting. Fortschr Röntgenstr 2021; 193: 527 – 536
The purpose of this study was to analyze size and growth dynamics of focal lesions (FL) as well as to quantify diffuse infiltration (DI) in untreated smoldering multiple myeloma (SMM) patients and ...correlate those MRI features with timepoint and cause of progression. We investigated 199 whole-body magnetic resonance imaging (wb-MRI) scans originating from longitudinal imaging of 60 SMM patients and 39 computed tomography (CT) scans for corresponding osteolytic lesions (OL) in 17 patients. All FLs >5 mm were manually segmented to quantify volume and growth dynamics, and DI was scored, rating four compartments separately in T1- and fat-saturated T2-weighted images. The majority of patients with at least two FLs showed substantial spatial heterogeneity in growth dynamics. The volume of the largest FL (
= 0.001, c-index 0.72), the speed of growth of the fastest growing FL (
= 0.003, c-index 0.75), the DI score (DIS,
= 0.014, c-index 0.67), and its dynamic over time (DIS dynamic,
< 0.001, c-index 0.67) all significantly correlated with the time to progression. Size and growth dynamics of FLs correlated significantly with presence/appearance of OL in CT within 2 years after the respective MRI assessment (
= 0.016 and
= 0.022). DIS correlated with decrease of hemoglobin (
< 0.001). In conclusion, size and growth dynamics of FLs correlate with prognosis and local bone destruction. Connections between MRI findings and progression patterns (fast growing FL-OL; DIS-hemoglobin decrease) might enable more precise diagnostic and therapeutic approaches for SMM patients in the future.
Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through ...metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab‐paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab‐paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab‐paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2) and cobicistat (150 mg) are fixed, three dose levels of nab‐paclitaxel (75, 100, and 125 mg/m2) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT‐Nr. 2019‐001439‐29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab‐paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large‐scale clinical study.
The purpose of this study was to assess how different MRI protocols (spinal vs. spinal plus pelvic vs. whole-body (wb)-MRI) affect staging in patients with smoldering multiple myeloma (SMM), ...according to the SLiM-CRAB-criterion ‘>1 focal lesion (FL) in MRI’. In this retrospective study, a baseline cohort of 147 SMM patients with wb-MRI at initial diagnosis was investigated, including prognostic data regarding development of CRAB-criteria. Fifty-two patients formed a follow-up cohort with a median of three wb-MRIs. The locations of all FLs were determined and it was calculated how staging decisions regarding the criterion ‘>1 FL in MRI’ would have been made if only a limited anatomic area (spine vs. spine plus pelvis) would have been covered by the MRI protocol. Furthermore, subgroups of patients selected by different cutoff-protocol-combinations were compared regarding their prognosis for development of CRAB-criteria. With an MRI protocol limited to spine/spine plus pelvis, only 28%/64% of patients who actually had >1 FL in wb-MRI would have been rated correctly as having ‘>1 FL in MRI’. Fifty-four percent/36% of patients with exactly 1 FL in spine/spine plus pelvis revealed >1 FL when the entire wb-MRI was analyzed. During follow-up, four more patients developed >1 FL in wb-MRI; both limited MRI protocols would have detected only one of these four patients as having >1 FL at the correct timepoint. Having >1 FL in spine/in spine plus pelvis/in the whole body was associated with a 43%/57%/49% probability of developing CRAB-criteria within 2 years. Patients with >3 FL in spine plus pelvis and patients with >4 FL in the whole body had an 80% probability to develop CRAB-criteria within 2 years. MRI protocols limited to the spine or to spine plus pelvis lead to substantial underdiagnoses of patients who actually have >1 FL in wb-MRI at baseline and during follow-up, which influences staging and treatment decisions according to the current SLiM-CRAB criteria. However, given the spatial distribution of FLs and the analysis on clinical course of patients indicates that the cutoff for the number of FLs should be adopted according to the MRI protocol when using MRI for staging in SMM.
Abstract
Purpose
For screening with low-dose CT (LDCT) to be effective, the benefits must outweigh the potential risks. In large lung cancer screening studies, a mortality reduction of approx. 20 % ...has been reported, which requires several organizational elements to be achieved in practice.
Materials and Methods
The elements to be set up are an effective invitation strategy, uniform and quality-assured assessment criteria, and computer-assisted evaluation tools resulting in a nodule management algorithm to assign each nodule the needed workup intensity. For patients with confirmed lung cancer, immediate counseling and guideline-compliant treatment in tightly integrated regional expert centers with expert skills are required. First, pulmonology contacts as well as CT facilities should be available in the participant’s neighborhood. IT infrastructure, linkage to clinical cancer registries, quality management as well as epidemiologic surveillance are also required.
Results
An effective organization of screening will result in an articulated structure of both widely distributed pulmonology offices as the participants’ primary contacts and CT facilities as well as central expert facilities for supervision of screening activities, individual clarification of suspicious findings, and treatment of proven cancer.
Conclusion
In order to ensure that the benefits of screening more than outweigh the potential harms and that it will be accepted by the public, a tightly organized structure is needed to ensure wide availability of pulmonologists as first contacts and CT facilities with expert skills and high-level equipment concentrated in central facilities.
Key Points:
For lung cancer screening, elements must function optimally and be tightly organized.
Lung cancer screening requires a network of expert centers and collaborating facilities.
IT infrastructure, QM, epidemiological surveillance, and linkage to cancer registries are essential.
Citation Format
Delorme S, Kaaks R: Lung Cancer Screening by Low-Dose Computed Tomography: Part 2 – Key Elements for Programmatic Implementation of Lung Cancer Screening. Fortschr Röntgenstr 2021; 193: 644 – 651
Purpose: In vitro sensitivity assays are promising tools to predict the individual outcome of different chemotherapy regimens. However, a direct
association between in vitro and in vivo ...chemosensitivity has to be shown by clinical studies. This multicenter phase II trial was aimed to investigate the efficacy
of a sensitivity-directed, first-line chemotherapy in metastasized melanoma patients, and to prove an association between
in vitro sensitivity and therapy outcome.
Patients and Methods: The primary study end point was objective response; secondary end points were safety, overall survival, and progression-free
survival. Viable tumor cells obtained from metastatic lesions were tested for chemosensitivity to seven single drugs and five
drug combinations using an ATP-based luminescence viability assay.
Results: Out of 82 recruited patients (intention-to-treat), 57 received assay-directed chemotherapy and 53 were evaluable for all
study end points (per protocol). The drug combinations used were gemcitabine + treosulfan, paclitaxel + cisplatin, paclitaxel
+ doxorubicin, and gemcitabine + cisplatin. The per protocol population could be divided into 22 (42%) chemosensitive and
31 (58%) chemoresistant patients by an arbitrary chemosensitivity index. Objective response was 36.4% in chemosensitive patients
compared with 16.1% in chemoresistant patients ( P = 0.114); progression arrest (complete response + partial response + stable disease) was 59.1% versus 22.6% ( P = 0.01). Chemosensitive patients showed an increased overall survival of 14.6 months compared with 7.4 months in chemoresistant
patients ( P = 0.041).
Conclusion: In vitro chemosensitivity testing may be worthy of further exploration to see if it could be a useful tool to predict the outcome
of melanoma patients treated with a sensitivity-directed chemotherapy. Therefore, these preliminary results will be evaluated
by a planned phase III trial using a randomized, standard-regimen controlled setting.
Purpose: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with high temporal resolution enables the detection of microcirculation
variables amplitude A and exchange rate constant k ep . ...In this study, the prognostic value of the DCE-MRI variables for overall survival and event-free survival in patients with
progressive multiple myeloma was investigated.
Experimental Design: Between 1999 and 2001, 65 patients with progressive or relapse of multiple myeloma requiring therapy were investigated with
DCE-MRI of the lumbar spine before start of therapy. The contrast uptake was quantified using a two-compartment model with
the output variables amplitude A and exchange rate constant k ep reflecting bone marrow microcirculation. The estimated median follow-up was 56 months. Event-free survival and overall survival
were investigated for DCE-MRI variables and for established prognosis variables (β 2 -microglobulin, lactate dehydrogenase, albumin, and age).
Results: Using a multivariate Cox regression model, β 2 -microglobulin and amplitude A of DCE-MRI were identified as statistically significant prognostic variable of event-free survival with P s of 0.01 and 0.02, respectively. A statistical correlation of DCE-MRI variables with overall survival could not be found.
The multivariate analysis of β 2 -microglobulin, age, lactate dehydrogenase, and albumin revealed β 2 -microglobulin as statistically significant prognostic factor for overall survival in this group of patients ( P < 0.001).
Conclusions: This analysis identifies contrast-enhanced DCE-MRI variable amplitude A reflecting increased bone marrow microcirculation and angiogenesis as a novel and possibly useful prognostic factor in patients
with multiple myeloma. Prospective studies are currently done to further investigate this functional variable for prognosis
and stratification of myeloma patients.
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