Purpose
Earlier work showed that IVIM‐NETorig, an unsupervised physics‐informed deep neural network, was faster and more accurate than other state‐of‐the‐art intravoxel‐incoherent motion (IVIM) ...fitting approaches to diffusion‐weighted imaging (DWI). This study presents a substantially improved version, IVIM‐NEToptim, and characterizes its superior performance in pancreatic cancer patients.
Method
In simulations (signal‐to‐noise ratio SNR = 20), the accuracy, independence, and consistency of IVIM‐NET were evaluated for combinations of hyperparameters (fit S0, constraints, network architecture, number of hidden layers, dropout, batch normalization, learning rate), by calculating the normalized root‐mean‐square error (NRMSE), Spearman’s ρ, and the coefficient of variation (CVNET), respectively. The best performing network, IVIM‐NEToptim was compared to least squares (LS) and a Bayesian approach at different SNRs. IVIM‐NEToptim’s performance was evaluated in an independent dataset of 23 patients with pancreatic ductal adenocarcinoma. Fourteen of the patients received no treatment between two repeated scan sessions and nine received chemoradiotherapy between the repeated sessions. Intersession within‐subject standard deviations (wSD) and treatment‐induced changes were assessed.
Results
In simulations (SNR = 20), IVIM‐NEToptim outperformed IVIM‐NETorig in accuracy (NRMSE(D) = 0.177 vs 0.196; NMRSE(f) = 0.220 vs 0.267; NMRSE(D*) = 0.386 vs 0.393), independence (ρ(D*, f) = 0.22 vs 0.74), and consistency (CVNET(D) = 0.013 vs 0.104; CVNET(f) = 0.020 vs 0.054; CVNET(D*) = 0.036 vs 0.110). IVIM‐NEToptim showed superior performance to the LS and Bayesian approaches at SNRs < 50. In vivo, IVIM‐NEToptim showed significantly less noisy parameter maps with lower wSD for D and f than the alternatives. In the treated cohort, IVIM‐NEToptim detected the most individual patients with significant parameter changes compared to day‐to‐day variations.
Conclusion
IVIM‐NEToptim is recommended for accurate, informative, and consistent IVIM fitting to DWI data.
Breast cancer is the most common type of cancer in women in the developed world. As a result of breast cancer treatment, many patients suffer from serious complaints in their arm and shoulder, ...leading to limitations in activities of daily living and participation. In this systematic literature review we present an overview of the adverse effects of the integrated breast cancer treatment related to impairment in functions and structures in the upper extremity and upper body and limitations in daily activities. Patients at highest risk were defined.
We conducted a systematic literature search using the databases of PubMed, Embase, CINAHL and Cochrane from 2000 to October 2012, according to the PRISMA guidelines. Included were studies with patients with stage I-III breast cancer, treated with surgery and additional treatments (radiotherapy, chemotherapy and hormonal therapy). The following health outcomes were extracted: reduced joint mobility, reduced muscle strength, pain, lymphedema and limitations in daily activities. Outcomes were divided in within the first 12 months and >12 months post-operatively. Patients treated with ALND are at the highest risk of developing impairments of the arm and shoulder. Reduced ROM and muscle strength, pain, lymphedema and decreased degree of activities in daily living were reported most frequently in relation to ALND. Lumpectomy was related to a decline in the level of activities of daily living. Radiotherapy and hormonal therapy were the main risk factors for pain.
Patients treated with ALND require special attention to detect and consequently address impairments in the arm and shoulder. Patients with pain should be monitored carefully, because pain limits the degree of daily activities. Future research has to describe a complete overview of the medical treatment and analyze outcome in relation to the treatment. Utilization of uniform validated measurement instruments has to be encouraged.
Trust in the oncologist is crucial for breast cancer patients. It reduces worry, enhances decision making, and stimulates adherence. Optimal nonverbal communication by the oncologist, particularly ...eye contact, body posture, and smiling, presumably benefits patients’ trust. We were the first to experimentally examine (1) how the oncologist’s nonverbal behavior influences trust, and (2) individual differences in breast cancer patients’ trust. Analogue patients (APs) viewed one out of eight versions of a video vignette displaying a consultation about chemotherapy treatment. All eight versions varied only in the oncologist’s amount of eye contact (consistent vs. inconsistent), body posture (forward leaning vs. varying), and smiling (occasional smiling vs. no smiling). Primary outcome was trust in the observed oncologist (Trust in Oncologist Scale). 214 APs participated. Consistent eye contact led to stronger trust (
β
= −.13,
p
= .04). This effect was largely explained by lower educated patients, for whom the effect of consistent eye contact was stronger than for higher educated patients (
β
= .18,
p
= .01). A forward leaning body posture did not influence trust, nor did smiling. However, if the oncologist smiled more, he was perceived as more friendly (
r
s
= .31,
p
< .001) and caring (
r
s
= .18,
p
= .01). Older (
β
= .17,
p
= .01) and lower educated APs (
β
= −.25,
p
< .001) were more trusting. Trust was weaker for more avoidantly attached APs (
β
= −.16,
p
= .03). We experimentally demonstrated the importance of maintaining consistent eye contact for breast cancer patients’ trust, especially among lower educated patients. These findings need to be translated into training for oncologists in how to optimize their nonverbal communication with breast cancer patients while simultaneously managing increased time pressure and computer use during the consultation.
Background
Palliative systemic treatment in patients with advanced or metastatic esophagogastric cancer may result in improved overall survival and quality of life but can also lead to considerable ...toxicity. In various cancer types, severe muscle mass depletion (sarcopenia) and poor muscle strength are associated with decreased survival and increased chemotherapy‐related toxicity. The aim of this study is to determine the impact of body composition on survival and chemotherapy toxicity in esophagogastric cancer patients treated with first‐line palliative chemotherapy.
Methods
A total of 88 patients with advanced esophagogastric cancer treated with standard first‐line palliative systemic therapy consisting of capecitabine and oxaliplatin (CapOx) between January 2010 and February 2017 were included. Skeletal muscle index (SMI), reflecting muscle mass, and skeletal muscle density (SMD), associated with muscle strength, were measured using pre‐treatment of all patients and evaluation computed tomography scans after three treatment cycles of 65 patients and were used to determine sarcopenia and sarcopenic obesity (i.e. sarcopenia and body mass index >25 kg/m2). The associations between body composition (SMI, SMD, sarcopenia, and sarcopenic obesity) and survival and toxicity were assessed using univariable and multivariable Cox and logistic regression analyses, respectively.
Results
Of 88 patients, 75% was male, and median age was 63 (interquartile range 56–69) years. The majority of patients had an adenocarcinoma (83%). Before start of treatment, 49% of the patients were sarcopenic, and 20% had sarcopenic obesity. Low SMD was observed in 50% of patients. During three cycles CapOx, SMI significantly decreased, with a median decrease of 4% (interquartile range −8.6–−0.4). Median progression‐free and overall survival were 6.9 and 10.1 months. SMI, SMD, sarcopenia, and sarcopenic obesity (both pre‐treatment and after three cycles) were neither associated with progression‐free nor overall survival. Pre‐treatment SMD was independently associated with grade 3–4 toxicity (odds ratio 0.94; 95% confidence interval 0.89–1.00) and sarcopenic obesity with grade 2–4 neuropathy (odds ratio 3.82; 95% confidence interval 1.20–12.18).
Conclusions
Sarcopenia was not associated with survival or treatment‐related toxicity in advanced esophagogastric cancer patients treated with CapOx. Pre‐treatment sarcopenic obesity was independently associated with the occurrence of grade 2–4 neurotoxicity and skeletal muscle density with grade 3–4 toxicity.
Local treatment (metastasectomy or stereotactic radiotherapy) for oligometastatic disease (OMD) in patients with esophagogastric cancer may improve overall survival (OS). The primary aim was to ...identify definitions of esophagogastric OMD. A secondary aim was to perform a meta-analysis of OS after local treatment versus systemic therapy alone for OMD.
Studies and study protocols reporting on definitions or OS after local treatment for esophagogastric OMD were included. The primary outcome was the maximum number of organs/lesions considered OMD and the maximum number of lesions per organ (i.e. 'organ-specific' OMD burden). Agreement was considered to be either absent/poor (< 50%), fair (50%–75%), or consensus (≥ 75%). The secondary outcome was the pooled adjusted hazard ratio (aHR) for OS after local treatment versus systemic therapy alone. The ROBINS tool was used for quality assessment.
A total of 97 studies, including 7 study protocols, and 2 prospective studies, were included. OMD was considered in 1 organ with ≤ 3 metastases (consensus). 'Organ-specific' OMD burden could involve bilobar ≤ 3 liver metastases, unilateral ≤ 2 lung metastases, 1 extra-regional lymph node station, ≤ 2 brain metastases, or bilateral adrenal gland metastases (consensus). Local treatment for OMD was associated with improved OS compared with systemic therapy alone based on 6 non-randomized studies (pooled aHR 0.47, 95% CI: 0.30–0.74) and for liver oligometastases based on 5 non-randomized studies (pooled aHR 0.39, 95% CI: 0.22–0.59). All studies scored serious risk of bias.
Current literature considers esophagogastric cancer spread limited to 1 organ with ≤ 3 metastases or 1 extra-regional lymph node station to be OMD. Local treatment for OMD appeared associated with improved OS compared with systemic therapy alone. Prospective randomized trials are warranted.
•Uniform definition of oligometastatic esophagogastric cancer is lacking.•1 organ with ≤3 metastatic lesions was considered oligometastatic (consensus).•Local treatment for oligometastases yields favorable overall survival.•Serious risk of bias in includes studies (all non-randomized).
Liquid biopsies are providing new opportunities for detection of residual disease in cell-free DNA (cfDNA) after surgery but may be confounded through identification of alterations arising from ...clonal hematopoiesis. Here, we identify circulating tumor-derived DNA (ctDNA) alterations through ultrasensitive targeted sequencing analyses of matched cfDNA and white blood cells from the same patient. We apply this approach to analyze samples from patients in the CRITICS trial, a phase III randomized controlled study of perioperative treatment in patients with operable gastric cancer. After filtering alterations from matched white blood cells, the presence of ctDNA predicts recurrence when analyzed within nine weeks after preoperative treatment and after surgery in patients eligible for multimodal treatment. These analyses provide a facile method for distinguishing ctDNA from other cfDNA alterations and highlight the utility of ctDNA as a predictive biomarker of patient outcome to perioperative cancer therapy and surgical resection in patients with gastric cancer.
Summary Background Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in ...patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years. Methods Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2–3N0–1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin AUC 2 mg/mL per min and intravenous paclitaxel 50 mg/m2 of body-surface area for 23 days) with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed. Findings Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84·1 months (range 61·1–116·8, IQR 70·7–96·6), median overall survival was 48·6 months (95% CI 32·1–65·1) in the neoadjuvant chemoradiotherapy plus surgery group and 24·0 months (14·2–33·7) in the surgery alone group (HR 0·68 95% CI 0·53–0·88; log-rank p=0·003). Median overall survival for patients with squamous cell carcinomas was 81·6 months (95% CI 47·2–116·0) in the neoadjuvant chemoradiotherapy plus surgery group and 21·1 months (15·4–26·7) in the surgery alone group (HR 0·48 95% CI 0·28–0·83; log-rank p=0·008); for patients with adenocarcinomas, it was 43·2 months (24·9–61·4) in the neoadjuvant chemoradiotherapy plus surgery group and 27·1 months (13·0–41·2) in the surgery alone group (HR 0·73 95% CI 0·55–0·98; log-rank p=0·038). Interpretation Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer. Funding Dutch Cancer Foundation (KWF Kankerbestrijding).
Abstract
Background
Lymphedema is a common complication of cancer treatment, resulting in swelling and subjective symptoms. Reliable and valid measurement of this side effect of medical treatment is ...important.
Purpose
The purpose of this study was to provide best evidence regarding which measurement instruments are most appropriate in measuring lymphedema in its different stages.
Data Sources
The PubMed and Web of Science databases were used, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed.
Study Selection
Clinical studies on measurement instruments assessing lymphedema were reviewed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) scoring instrument for quality assessment.
Data Extraction
Data on reliability, concurrent validity, convergent validity, sensitivity, specificity, applicability, and costs were extracted.
Data Synthesis
Pooled data showed good intrarater intraclass correlation coefficients (ICCs) (.89) for bioimpedance spectroscopy (BIS) in the lower extremities and high intrarater and interrater ICCs for water volumetry, tape measurement, and perometry (.98–.99) in the upper extremities. In the upper extremities, the standard error of measurement was 3.6% (σ=0.7%) for water volumetry, 5.6% (σ=2.1%) for perometry, and 6.6% (σ=2.6%) for tape measurement. Sensitivity of tape measurement in the upper extremities, using different cutoff points, varied from 0.73 to 0.90, and specificity values varied from 0.72 to 0.78.
Limitations
No uniform definition of lymphedema was available, and a gold standard as a reference test was lacking. Items concerning risk of bias were study design, patient selection, description of lymphedema, blinding of test outcomes, and number of included participants.
Conclusions
Measurement instruments with evidence for good reliability and validity were BIS, water volumetry, tape measurement, and perometry, where BIS can detect alterations in extracellular fluid in stage 1 lymphedema and the other measurement instruments can detect alterations in volume starting from stage 2. In research, water volumetry is indicated as a reference test for measuring lymphedema in the upper extremities.
Although radical surgery remains the cornerstone of cure in resectable gastric cancer, survival remains poor. Current evidence-based (neo)adjuvant strategies have shown to improve outcome, including ...perioperative chemotherapy, postoperative chemoradiotherapy and postoperative chemotherapy. However, these regimens suffer from poor patient compliance, particularly in the postoperative phase of treatment. The CRITICS-II trial aims to optimize preoperative treatment by comparing three treatment regimens: (1) chemotherapy, (2) chemotherapy followed by chemoradiotherapy and (3) chemoradiotherapy.
In this multicentre phase II non-comparative study, patients with clinical stage IB-IIIC (TNM 8th edition) resectable gastric adenocarcinoma are randomised between: (1) 4 cycles of docetaxel+oxaliplatin+capecitabine (DOC), (2) 2 cycles of DOC followed by chemoradiotherapy (45Gy in combination with weekly paclitaxel and carboplatin) or (3) chemoradiotherapy. Primary endpoint is event-free survival, 1 year after randomisation (events are local and/or regional recurrence or progression, distant recurrence, or death from any cause). Secondary endpoints include: toxicity, surgical outcomes, percentage radical (R0) resections, pathological tumour response, disease recurrence, overall survival, and health related quality of life. Exploratory endpoints include translational studies on predictive and prognostic biomarkers.
The aim of this study is to select the most promising among three preoperative treatment arms in patients with resectable gastric adenocarcinoma. This treatment regimen will subsequently be compared with the standard therapy in a phase III trial.
clinicaltrials.gov NCT02931890 ; registered 13 October 2016. Date of first enrolment: 21 December 2017.
Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor ...outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6–producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.
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