The IDEA trial showed no clinical relevant differences in efficacy between 3 and 6 months of oxaliplatin‐based adjuvant chemotherapy (ACT) in colon cancer (CC), while toxicity was substantially lower ...in the 3 months regimen. Therefore, in 2017 the Dutch colorectal cancer guideline was revised and currently recommends 3 months of oxaliplatin‐based ACT. Furthermore, the definition of high‐risk stage II CC was restricted to pT4 tumors. We analyzed changes in ACT between 2015 and 2019. From the Netherlands Cancer Registry all 16 721 patients ≥18 years with resected high‐risk stage II and stage III CC during 2015 to 2019 were selected. Differences in patient and treatment characteristics were analyzed per calendar year according to stage and age. Mean duration of oxaliplatin‐based ACT decreased from 18.6 (±8.0) to 9.5 (±3.8) weeks between 2015 and 2019. In patients receiving ACT (n = 8170), the proportion treated with oxaliplatin increased from 74% to 83%. The proportion of patients receiving ACT was stable, 61% to 69% in stage III and 26% to 29% in pT4 stage II. ACT in previous high‐risk pT3N0 disease decreased from 15% to 3%. Use of oxaliplatin increased from 27% to 49% in patients aged ≥75 years. The revised guideline was rapidly implemented and led to an increase in oxaliplatin‐based ACT in the elderly and increased guideline‐adherence in high‐risk stage II CC.
What's new?
Results from the 2017 International Duration Evaluation of Adjuvant Chemotherapy Collaboration (IDEA) trial support the use of adjuvant chemotherapy (ACT) for 3 months in stage II and III colon cancer patients. Our study examined the impact of the incorporation of IDEA trial results into colon cancer treatment guidelines in the Netherlands. Analyses of Netherlands Cancer Registry data show that rapid guideline implementation shortened ACT duration, increased oxaliplatin‐based ACT in elderly patients, and increased guideline‐adherence in stage II disease. Shorter treatment duration can reduce toxicity and costs. The findings highlight the value of rapid translation of scientific insights into clinical care.
Identification of non-metastatic colorectal cancer (CRC) patients with a high risk of recurrence after tumor resection is important to select patients who might benefit from adjuvant treatment. ...Cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) analyses after surgery are promising biomarkers to predict recurrence in these patients. However, these analyses face several challenges and do not allow guidance of neoadjuvant treatment, which might become a novel standard option in colon cancer treatment. The prognostic value of cfDNA/ctDNA before surgery is unclear. This systematic review aims to provide an overview of publications in which the prognostic value of presurgery cfDNA/ctDNA in non-metastatic CRC patients was studied and is performed according to PRISMA guidelines. A total of 29 out of 1233 articles were included and categorized into three groups that reflect the type of approach: measurement of cfDNA, ctDNA somatic alterations, and ctDNA methylation. Overall, a clear association between presurgery cfDNA/ctDNA and the outcome was not observed, but large studies that primarily focus on the prognostic value of presurgery cfDNA/ctDNA are lacking. Designing and performing studies that focus on the value of presurgery cfDNA/ctDNA is needed, in addition to standardization in the reporting of cfDNA/ctDNA results according to existing guidelines to improve comparability and interpretation among studies.
IMPORTANCE: The role of primary tumor resection (PTR) in synchronous patients with metastatic colorectal cancer (mCRC) who had unresectable metastases and few or absent symptoms of their primary ...tumor is unclear. Studying subgroups with low postoperative mortality may identify patients who potentially benefit from PTR. OBJECTIVE: To determine the difference in 60-day mortality between patients randomized to systemic treatment only vs PTR followed by systemic treatment, and to explore risk factors associated with 60-day mortality. DESIGN, SETTING, AND PARTICIPANTS: CAIRO4 is a randomized phase 3 trial initiated in 2012 in which patients with mCRC were randomized to systemic treatment only or PTR followed by systemic treatment with palliative intent. This multicenter study was conducted by the Danish and Dutch Colorectal Cancer Group in general and academic hospitals in Denmark and the Netherlands. Patients included between August 2012 and December 2019 with histologically proven colorectal cancer, unresectable metastases, and a primary tumor with few or absent symptoms were eligible. INTERVENTIONS: Systemic treatment, consisting of fluoropyrimidine-based chemotherapy with bevacizumab vs PTR followed by fluoropyrimidine-based chemotherapy with bevacizumab. MAIN OUTCOMES AND MEASURES: The aim of the current analysis was to compare 60-day mortality rates in both treatment arms. A secondary aim was the identification of risk factors for 60-day mortality in the treatment arms. These aims were not predefined in the study protocol. RESULTS: A total of 196 patients were included in the intention-to-treat analysis (112 57% men; median IQR age, 65 59-70 years). Sixty-day mortality was 3% (95% CI, 1%-9%) in the systemic treatment arm and 11% (95% CI, 6%-19%) in the PTR arm (P = .03). In a per-protocol analysis, 60-day mortality was 2% (95% CI, 1%-7%) vs 10% (95% CI, 5%-18%; P = .048). Patients with elevated serum levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and/or neutrophils who were randomized to PTR had a significantly higher 60-day mortality than patients without these characteristics. CONCLUSIONS AND RELEVANCE: Patients with mCRC who were randomized to PTR followed by systemic treatment had a higher 60-day mortality than patients randomized to systemic treatment. Especially patients randomized to the PTR arm with elevated serum levels of lactate dehydrogenase, neutrophils, aspartate aminotransferase, and/or alanine aminotransferase were at high risk of postoperative mortality. Final study results on overall survival have to be awaited. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01606098
Phosphatidylserine exposure by red blood cells is acknowledged as a signal that initiates phagocytic removal of the cells from the circulation. Several disorders and conditions are known to induce ...phosphatidylserine exposure. Removal of phosphatidylserine-exposing red blood cells generally occurs by macrophages in the spleen and liver. Previously, however, we have shown that endothelial cells are also capable of erythrophagocytosis. Key players in the erythrophagocytosis by endothelial cells appeared to be lactadherin and α(v)-integrin. Phagocytosis via the phosphatidylserine-lactadherin-α(v)-integrin pathway is the acknowledged route for removal of apoptotic innate cells by phagocytes.
Endothelial cell phagocytosis of red blood cells was further explored using a more (patho)physiological approach. Red blood cells were exposed to oxidative stress, induced by tert-butyl hydroperoxide. After opsonization with lactadherin, red blood cells were incubated with endothelial cells to study erythrophagocytosis and examine cytotoxicity.
Red blood cells exposed to oxidative stress show alterations such as phosphatidylserine exposure and loss of deformability. When incubated with endothelial cells, marked erythrophagocytosis occurred in the presence of lactadherin under both static and flow conditions. As a consequence, intracellular organization was disturbed and endothelial cells were seen to change shape ('rounding up'). Increased expression of apoptotic markers indicated that marked erythrophagocytosis has cytotoxic effects.
Activated endothelial cells show significant phagocytosis of phosphatidylserine-exposing and rigid red blood cells under both static and flow conditions. This results in a certain degree of cytotoxicity. We postulate that activated endothelial cells play a role in red blood cell clearance in vivo. Significant erythrophagocytosis can induce endothelial cell loss, which may contribute to vasopathological effects as seen, for instance, in sickle cell disease.
Abstract Background Studies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the ...relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity, functional iron availability and hepcidin. Methods and Results In the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome (EPOCARES) study, which investigates the role of EPO in 54 iron-supplemented anemic patients with CHF and chronic kidney disease (CKD) (n = 35 treated with 50 IU/kg/wk Epopoetin beta, n = 19 control), RDW was not associated with EPO resistance. We defined EPO resistance by EPO levels ( r = 0.12, P = .42), the observed/predicted log EPO ratio ( r = 0.12, P = .42), the increase in reticulocytes after 2 weeks of EPO treatment ( r = −0.18, P = .31), and the increase of hemoglobin after 6 months of EPO treatment ( r = 0.26, P = .35). However, RDW was negatively correlated with functional iron availability (reticulocyte hemoglobin content, r = −0.48, P < .001, and transferrin saturation, r = −0.39, P = .005) and positively with erythropoietic activity (soluble transferrin receptor, r = 0.48, P < .001, immature reticulocyte fraction, r = 0.36, P = .01) and positively with interleukin-6 ( r = 0.48, P < .001). No correlation existed between hepcidin-25 and RDW. Conclusions EPO resistance was not associated with RDW. RDW was associated with functional iron availability, erythropoietic activity, and interleukin-6 in anemic patients with CHF and CKD.
Uncertainty exists about a possible survival benefit of primary tumor resection (PTR) in synchronous metastatic colon cancer (mCC). Since sidedness of the primary tumor is regarded as an important ...prognostic factor, our objective was to study the interaction between PTR and sidedness in synchronous mCC.
In this retrospective study, we used data from 2 first-line phase 3 randomized controlled trials (RCTs). A mixed Cox regression model was used to study the multiplicative interaction between PTR and sidedness. We adjusted for age, treatment arm, WHO performance status, number of affected organs by metastases, serum lactate dehydrogenase, and year of enrollment.
We found that PTR is associated with better survival in both right-sided (hazard ratio HR 0.59 95% confidence interval 0.42-0.8 2) and left-sided mCC (HR 0.70 95% confidence interval 0.52-0.93). The interaction between PTR and sidedness was not significant (p = 0.45).
Our data suggest that the prognostic value of PTR is independent of sidedness. Validation of these results will be performed in ongoing RCTs.
Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer
. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. ...Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.
Abstract
Background Accurate detection of patients with minimal residual disease (MRD) after resection of localized colon cancer remains an unmet clinical need as these patients might benefit from ...adjuvant chemotherapy (ACT). For stage II colon cancer, ACT is only indicated in patients with a pT4 tumor without a deficient mismatch repair system (dMMR), according to Dutch guidelines. However, recurrence rate (RR) in stage II colon cancer is still 15-20%. Circulating tumor DNA (ctDNA), consisting of small fragments of DNA containing tumor-specific mutations, has been shown to be a promising biomarker for MRD and a strong predictor for recurrent disease when detectable after resection. The MEDOCC-CrEATE trial investigates how many stage II colon cancer patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces RR in these patients.
Methods The MEDOCC-CrEATE study follows the ‘trials within cohorts' (TwiCs) design. Patients with colorectal cancer are included in the Prospective Dutch ColoRectal Cancer (PLCRC) cohort study and give informed consent for collection of clinical data and biomaterials, including tissue and blood samples. Additionally, patients are invited to give their consent for future randomization without being informed when allocated to the control group receiving standard of care. In MEDOCC-CrEATE 1320 stage II colon cancer patients without an indication for ACT will be included and randomized 1:1 into an experimental and a control arm. In the experimental arm, tissue and blood samples are analyzed after surgery for tissue-informed detection of plasma ctDNA, using the PGDx elio™ Platform. Patients with detectable ctDNA after surgery will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin. Patients in the experimental arm without detectable ctDNA and patients in the control arm receive standard follow-up. The primary endpoint is the proportion of patients accepting ACT when ctDNA is detectable after resection. Most important secondary endpoint is 2-year RR, but also includes 5-year RR, disease free and overall survival, time to recurrence, quality of life and cost-effectiveness of the ctDNA-based treatment strategy. Data will be analyzed by intention to treat. To our knowledge, MEDOCC-CrEATE is the first trial in which a ctDNA guided strategy for adjuvant chemotherapy in colon cancer is investigated. The first patient was enrolled in August 2020. MEDOCC-CrEATE is now open for inclusion in 8 hospitals in the Netherlands. So far, 9 patients have been randomized. The number of participating hospitals will be expanded to 20-25 hospitals to include all 1320 patients within 3 years. MEDOCC-CrEATE has been registered in the Netherlands Trial Register: NL6281/NTR6455.
Citation Format: Suzanna J. Schraa, Karlijn L. Van Rooijen, Dave E. Van Der Kruijssen, Carmen Rubio Alarcón, Jillian Phallen, John Simmons, Sam Angiuoli, Amy E. Greer, Veerle M. Coupé, Helma M. Van Grevenstein, Sjoerd Elias, Helena M. Verkooijen, Miranda M. Van Dongen, Linda J. Bosch, Daan Van Den Broek, Gerrit A. Meijer, Victor E. Velculescu, Remond J. Fijneman, Geraldine R. Vink, Miriam Koopman. MEDOCC-CrEATE trial in progress: effectiveness of adjuvant chemotherapy in stage II colon cancer patients with positive circulating tumor DNA abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT251.
Abstract
Purpose
The field of circulating cell free DNA (cfDNA) testing is quickly developing. Multiple platforms to detect hotspot mutations in ctDNA are available, including Bio-Rad droplet digital ...PCR (ddPCR), BioCartis Idylla, Roche COBAS z480 and Sysmex BEAMing. These platforms vary in the amount of plasma required, the method of ctDNA isolation, the number of hotspots analyzed, and the costs per sample. These factors can impact the applicability of a specific platform in the analysis of ctDNA.
In this study we compared these platforms in terms of sensitivity and total costs per sample.
Methods
The platform comparison was performed as follows:
1. Plasma from six metastatic colorectal cancer (mCRC) patients with known tissue KRAS mutation status was analyzed according to the manufacturers’ protocols.
2. Sensitivity was tested using six constructed reference samples with seven KRAS hotspot mutations at various total input (10ng, 50ng) and mutant allele frequencies (0%, 0.04%, 0.50%); each in four replicates.
3. Twelve mCRC patients were analyzed using equal amounts of ctDNA for each platform.
4. Total costs per sample were evaluated, including costs for consumables, technician hands-on time, equipment and maintenance.
Results
1. In six mCRC samples BEAMing (3ml plasma) detected 5/6 mutations, ddPCR and Idylla (both 1ml plasma) 4/6 mutations and COBAS z480 (2ml plasma) 3/6 mutations.
2. In constructed reference samples ddPCR (65%) and BEAMing (46%) yielded the highest sensitivity. With 10ng input BEAMing and COBAS z480 produced “Too little DNA” errors in 60% and 100% of cases, respectively.
3. In twelve mCRC samples, eight had more than 10ng ctDNA and four had less. All platforms were fully concordant for samples with more than 10ng input. Detection rate across twelve samples: Idylla detected 7/11 detectable mutations, COBAS z480 and BEAMing both detected 5/11, ddPCR detected 4/10.
4. BEAMing has the highest cost per sample (€486-€821) whereas ddPCR has the lowest cost per sample (€39-€298).
Conclusions
A direct comparison of ctDNA mutation detection platforms is complex and should take into account the differences in input and output specifications of the platforms.
Factors such as complexity of analysis (Idylla is a low complexity platform, whereas BEAMing requires more specialized training), total costs (varying from ddPCR to BEAMing), sensitivity (ddPCR and BEAMing yielded the highest sensitivity) and the number of mutations evaluated vary greatly between the platforms. All these factors influence ctDNA analysis and will have to be considered when choosing a specific platform for a specific (clinical) question, or when comparing results between studies.
Our data provide insight in the comparative performance of four commercial ctDNA analysis platforms, allowing future users to make an informed decision regarding a platform.
Acknowledgement
Powered by Health~Holland, Top Sector Life Sciences & Health, grant LSHM16047-H005.
Citation Format: Daan C. Vessies, Marjolein J. Greuter, Karlijn L. van Rooijen, Theodora C. Linders, Mirthe Lanfermeijer, Kalpana L. Ramkisoensing, Flore E. Grijseels, Boris van Doorn, Gerrit A. Meijer, Miriam Koopman, Veerle M. Coupé, Geraldine R. Vink, Remond J. Fijneman, Daan van den Broek. Performance and cost comparison of circulating tumor DNA detection platforms abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2276.
IMPORTANCE: Triplet chemotherapy with fluorouracil, folinic acid, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-B) is an effective first-line treatment option for patients with metastatic ...colorectal cancer (mCRC). However, the degree of implementation of FOLFOXIRI-B in daily practice is unknown. OBJECTIVES: To evaluate the current adoption rate of FOLFOXIRI-B in patients with mCRC and investigate the perspectives of medical oncologists toward this treatment option. DESIGN, SETTING, AND PARTICIPANTS: This 1-week, multicenter, cross-sectional study in the Netherlands used a flash mob design, which facilitates ultrafast data generation (flash) through the engagement of numerous researchers (mob). During the study week (March 1-5, 2021), patient data were retrieved from electronic health records of 47 hospitals on patients with mCRC who were referred to a medical oncologist between November 1, 2020, and January 31, 2021. Interviews were simultaneously conducted with 101 medical oncologists from 52 hospitals who regularly treat patients with mCRC. EXPOSURE: First-line systemic treatment as determined by the treating physician. MAIN OUTCOMES AND MEASURES: The FOLFOXIRI-B prescription rate was the main outcome. Current practice was compared with prescription rates in 2015 to 2018. Eligibility for treatment with FOLFOXIRI-B was estimated. An exploratory outcome was medical oncologists’ reported perspectives on FOLFOXIRI-B. RESULTS: A total of 5948 patients in the Netherlands (median age interquartile range, 66 57-73 years; 3503 59% male; and 3712 62% with left-sided or rectal tumor) were treated with first-line systemic therapy for synchronous mCRC. A total of 282 patients with mCRC underwent systemic therapy during the study period (2021). Of these 282 patients, 199 (71%) were treated with intensive first-line therapy other than FOLFOXIRI-B, of whom 184 (65%) were treated with oxaliplatin doublets with or without bevacizumab; 14 (5%) with irinotecan doublets with or without bevacizumab, panitumumab, or cetuximab; and 1 (0.4%) with irinotecan with bevacizumab. Fifty-four patients (19%) were treated with fluoropyrimidine monotherapy with or without bevacizumab, 1 patient (0.4%) with panitumumab monotherapy, and 3 (1%) with immune checkpoint inhibitors. In total, 25 patients (9%; 95% CI, 6%-12%) were treated with first-line FOLFOXIRI-B compared with 142 (2%; 95% CI, 2%-3%) in 2015 to 2018. During the study period, 21 of 157 eligible patients (13.4%) in the Netherlands were treated with FOLFOXIRI-B. A total of 87 medical oncologists (86%) reported discussing FOLFOXIRI-B as a treatment option with eligible patients. A total of 47 of 85 (55%) generally communicated a preference for a chemotherapy doublet to patients. These oncologists reported a significantly lower awareness of guidelines and trial results. Toxic effects were the most reported reason to prefer an alternative regimen. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that FOLFOXIRI-B prescription rates have marginally increased in the last 5 years. Considering that most medical oncologists discuss this treatment option, the prescription rate found in this study was below expectations. Awareness of guidelines and trial data seems to contribute to the discussion of available treatment options by medical oncologists, and the findings of this study suggest a need for repeated and continuing medical education.
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