Budget Impact Analysis of Circulating Tumor DNA Testing for Colon Cancer in Commercial Health and Medicare Advantage Plans.

Importance: In a randomized clinical trial, treatment guided by tumor-informed circulating tumor (ct)DNA testing reduced adjuvant chemotherapy use without compromising recurrence-free survival in patients with stage II colon cancer. The potential effects of adopting ctDNA testing into routine patient care is unknown. Objective: To compare the total cost of patient care scenarios with and without the adoption of ctDNA testing. Design, Setting, and Participants: This budget impact analysis was conducted from the perspectives of US commercial health and Medicare Advantage payers. A decision-analytical model was populated with age-specific incidence of colon cancer, use of adjuvant chemotherapy, and use of single-agent or multiagent regimens. Total cost was estimated with the costs of ctDNA testing, drug acquisition, administration, surveillance, and adverse events. The analysis was conducted from September 2023 to January 2024. Exposures: The adoption of ctDNA testing. Main Outcomes and Measures: The incremental cost in the first year following the adoption of ctDNA testing, where testing will affect patient treatment and costs. Results: In hypothetical plans with 1 million individuals covered, 35 commercial health plan members and 102 Medicare Advantage members aged 75 years and younger were eligible for ctDNA testing. In the base case with a 50% adoption rate, total cost savings were $221 684 (equivalent to $0.02 per member per month [PMPM]) for a commercial payer and $116 720 (equivalent to $0.01 PMPM) for a Medicare Advantage payer. Cost savings were robust to variations in assumptions of all parameters in the commercial population but sensitive to variations in assumptions of adjuvant chemotherapy use rates in the Medicare Advantage population. The number needed to test to avoid 1 patient receiving adjuvant chemotherapy was 4 in the commercial population and 10 in the Medicare Advantage population. The budget-neutral cost for ctDNA testing was $16 202 for a commercial payer and $5793 for a Medicare Advantage payer. Conclusions and Relevance: Use of tumor-informed ctDNA testing to guide adjuvant chemotherapy in postsurgery patients with stage II colon cancer was projected to result in cost savings for both commercial and Medicare Advantage payers. Adoption of ctDNA testing is therefore advantageous from a budgetary perspective.

Assessment of the Anti-Cancer Efficiency of Silver Moringa oleifera Leaves Nano-extract against Colon Cancer Induced Chemically in Rats.

BACKGROUND: Colorectal cancer (CRC) categorized as the most common type of gastrointestinal cancers affected both genders equally. Chemotherapeutic drugs became limited due to their deleterious side effects. Therefore, efficiency of M. oleifera leaves extract increased by incorporating silver nanoparticles (Ag-NPs) then studied against colon cancer induced by azoxymethane (AOM) in rats. METHODS: Different hematological and biochemical measurements in addition to specific tumor and inflammatory markers were quantified. Histopathological examination for Colonic tissues was performed. Native proteins and isoenzyme patterns were electrophoretically detected in addition to assaying expression of Tumor Protein P53 (TP53) and Adenomatous Polyposis Coli (APC) genes in colonic tissues. RESULTS: M. oleifera nano-extract restored levels of the hematological and biochemical measurements in addition to levels of tumor and inflammatory markers to normalcy in both of nano-extract simult- and post-treated groups. Also, it minimized severity of the histopathological alterations in the simult-treated group and prevented it completely in the post-treated group. The lowest similarity index (SI%) values were noticed with electrophoretic protein (SI=61.54%), lipid (SI=0.00%) and calcium (SI=75.00%) moieties of protein patterns, catalase (SI=85.71%), peroxidase (SI=85.71%), α-esterase (SI=50.00%) and ß-esterase (SI=50.00%) isoenzymes in addition to altering the relative quantities of total protein and isoenzyme bands in colon of cancer induced group. Moreover, levels of TP53 and APC gene expression increased significantly (P≤0.05) in colon cancer induced group. The nano-extract prevented the qualitative and quantitative alterations in the different electrophoretic patterns in addition to restoring levels of the gene expressions to normalcy in both of simult- and post-treated groups. CONCLUSION: M. oleifera nano-extract exhibited ameliorative effect against the biochemical, physiological and molecular alterations induced by AOM in nano-extract simult- and post-treated groups.
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Circulating tumor DNA guided adjuvant chemotherapy in stage II colon cancer (MEDOCC-CrEATE): study protocol for a trial within a cohort study.

BACKGROUND: Accurate detection of patients with minimal residual disease (MRD) after surgery for stage II colon cancer (CC) remains an urgent unmet clinical need to improve selection of patients who might benefit form adjuvant chemotherapy (ACT). Presence of circulating tumor DNA (ctDNA) is indicative for MRD and has high predictive value for recurrent disease. The MEDOCC-CrEATE trial investigates how many stage II CC patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces the risk of recurrence in these patients. METHODS/DESIGN: MEDOCC-CrEATE follows the 'trial within cohorts' (TwiCs) design. Patients with colorectal cancer (CRC) are included in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) and give informed consent for collection of clinical data, tissue and blood samples, and consent for future randomization. MEDOCC-CrEATE is a subcohort within PLCRC consisting of 1320 stage II CC patients without indication for ACT according to current guidelines, who are randomized 1:1 into an experimental and a control arm. In the experimental arm, post-surgery blood samples and tissue are analyzed for tissue-informed detection of plasma ctDNA, using the PGDx elio™ platform. Patients with detectable ctDNA will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin while patients without detectable ctDNA and patients in the control group will standard follow-up according to guideline. The primary endpoint is the proportion of patients receiving ACT when ctDNA is detectable after resection. The main secondary outcome is 2-year recurrence rate (RR), but also includes 5-year RR, disease free survival, overall survival, time to recurrence, quality of life and cost-effectiveness. Data will be analyzed by intention to treat. DISCUSSION: The MEDOCC-CrEATE trial will provide insight into the willingness of stage II CC patients to be treated with ACT guided by ctDNA biomarker testing and whether ACT will prevent recurrences in a high-risk population. Use of the TwiCs design provides the opportunity to randomize patients before ctDNA measurement, avoiding ethical dilemmas of ctDNA status disclosure in the control group. TRIAL REGISTRATION: Netherlands Trial Register: NL6281/NTR6455 . Registered 18 May 2017, https://www.trialregister.nl/trial/6281.

Health and Economic Impact of Intensive Surveillance for Distant Recurrence After Curative Treatment of Colon Cancer: A Mathematical Modeling Study.

BACKGROUND: Intensive surveillance strategies are currently recommended for patients after curative treatment of colon cancer, with the aim of secondary prevention of recurrence. Yet, intensive surveillance has not yielded improvements in overall patient survival compared with minimal follow-up, and more intensive surveillance may be costlier. OBJECTIVE: The purpose of this study was to estimate the quality-adjusted life-years, economic costs, and cost-effectiveness of various surveillance strategies after curative treatment of colon cancer. DESIGN: A Markov model was calibrated to reflect the natural history of colon cancer recurrence and used to estimate surveillance costs and outcomes. SETTINGS: This was a decision-analytic model. PATIENTS: Individuals entered the model at age 60 years after curative treatment for stage I, II, or III colon cancer. Other initial age groups were assessed in secondary analyses. MAIN OUTCOME MEASURES: We estimated the gains in quality-adjusted life-years achieved by early detection and treatment of recurrence, as well as the economic costs of surveillance under various strategies. RESULTS: Cost-effective strategies for patients with stage I colon cancer improved quality-adjusted life-expectancy by 0.02 to 0.06 quality-adjusted life-years at an incremental cost of $1702 to $13,019. For stage II, they improved quality-adjusted life expectancy by 0.03 to 0.09 quality-adjusted life-years at a cost of $2300 to $14,363. For stage III, they improved quality-adjusted life expectancy by 0.03 to 0.17 quality-adjusted life-years for a cost of $1416 to $17,631. At a commonly cited willingness-to-pay threshold of $100,000 per quality-adjusted life-year, the most cost-effective strategy for patients with a history of stage I or II colon cancer was liver ultrasound and chest x-ray annually. For those with a history of stage III colon cancer, the optimal strategy was liver ultrasound and chest x-ray every 6 months with CEA measurement every 6 months. LIMITATIONS: The study was limited by model structure assumptions and uncertainty around the values of the model's parameters. CONCLUSIONS: Given currently available data and within the limitations of a model-based decision-analytic approach, the effectiveness of routine intensive surveillance for patients after treatment of colon cancer appears, on average, to be small. Compared with testing using lower cost imaging, currently recommended strategies are associated with cost-effectiveness ratios that indicate low value according to well-accepted willingness-to-pay thresholds in the United States. See Video Abstract at http://links.lww.com/DCR/A921.

Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity.

Improving early detection of colorectal cancer (CRC) is a key public health priority as adenomas and stage I cancer can be treated with minimally invasive procedures. Population screening strategies based on detection of occult blood in the feces have contributed to enhance detection rates of localized disease, but new approaches based on genetic analyses able to increase specificity and sensitivity could provide additional advantages compared to current screening methodologies. Recently, circulating cell-free DNA (cfDNA) has received much attention as a cancer biomarker for its ability to monitor the progression of advanced disease, predict tumor recurrence and reflect the complex genetic heterogeneity of cancers. Here, we tested whether analysis of cfDNA is a viable tool to enhance detection of colon adenomas. To address this, we assessed a cohort of patients with adenomas and healthy controls using droplet digital PCR (ddPCR) and mutation-specific assays targeted to trunk mutations. Additionally, we performed multiregional, targeted next-generation sequencing (NGS) of adenomas and unmasked extensive heterogeneity, affecting known drivers such as APC, KRAS and mismatch repair (MMR) genes. However, tumor-related mutations were undetectable in patients' plasma. Finally, we employed a preclinical mouse model of Apc-driven intestinal adenomas and confirmed the inability to identify tumor-related alterations via cfDNA, despite the enhanced disease burden displayed by this experimental cancer model. Therefore, we conclude that benign colon lesions display extensive genetic heterogeneity, that they are not prone to release DNA into the circulation and are unlikely to be reliably detected with liquid biopsies, at least with the current technologies.

Screening of KRAS Mutation in Pre- and Post-Surgery Serum of Patients Suffering from Colon Cancer by COLD-PCR HRM.

Genomic characterization of cell-free circulating tumour DNA (ctDNA) may offer an opportunity to assess clonal dynamics throughout the course of a patient's illness. The existence of KRAS driver mutations in colon cancer patients is determinant to decide their treatment and to predict their outcome. DNA is extracted automatically from 400 µL of serum using the MagNa Pure Compact with the Nucleic Acid Isolation Kit I. DNA amplification, COLD-PCR and HRM were performed in the same run in the Light Cycler 480.We found three different situations: pre- and post-surgical samples grouped with the negative control, pre-surgical samples appear to group with the positive control and the post-surgical samples appear to group with the negative control and finally both samples, pre- and post-surgical ones, appear to be grouped with the positive control. COLD-PCR HRM is a cost-effective way for screening one of the most common driver mutations to predict the worst prognosis in colorectal cancer.

[ASSESSMENT OF EFFICACY OF MELATONIN IN SURGICAL TREATMENT OF COLON TUMORS].

Melatonin is neurohormone, which is involved in regulation of many functions of an organism, including the digestive system. Therefore the authors offered to include this hormone as a preconditioner factor in surgical treatment of colon tumors using laparotomy and laparoscopy. Preoperative application of melatonin allowed shortening the terms of postoperative period and hospital stay.

Endo-ß-N-acetylglucosaminidase H de-N-glycosylation in a domestic microwave oven: application to biomarker discovery.

Sample preparation is the rate-limiting step in glycan analysis workflows. Among all of the steps, enzymatic digestions, which are usually performed overnight, are the most time-consuming. In the current study, we report an economical and fast preparation of N-glycans from serum, including microwave-assisted enzymatic digestion in the absence of denaturing chemicals and solvents during the release. To this end, we used a household microwave oven to accelerate both pronase and endo-ß-N-acetylglucosaminidase H (Endo H) digestions. Purification was then performed using self-made SP20SS and carbon tips. We were able to prepare samples in 55 min instead of 21 h. Finally, the method was applied in the context of oncological biomarker discovery exemplarily to ovarian and colon cancer. We observed a significant downregulation of sialylated hybrid structures in ovarian cancer samples using capillary electrophoresis-laser-induced fluorescence (CE-LIF). Furthermore, sepsis, a systemic inflammatory response syndrome, was also included in the study to understand whether the changes observed in ovarian cancer patients were due to the cancer itself or to the inflammation that usually accompanies its development. Because sialylated hybrid structures were upregulated in sepsis samples, the downregulation of these structures in ovarian cancer is specific to the cancer itself and, therefore, could be used as a biomarker.

Lower albumin levels in African Americans at colon cancer diagnosis: a potential explanation for outcome disparities between groups?

BACKGROUND AND AIM: Colorectal cancer is the third most common cancer and 3rd leading cause of cancer-related death in the USA. African Americans (AA) have inferior outcomes when matched for diagnosis stage and socioeconomic situation. Nutritional status, at diagnosis and its contribution to the observed cancer outcome disparity, between AA and non-Hispanic whites (nHw) has not been evaluated to date. The aim of the investigation was to determine if differences in nutritional surrogate markers, such as serum albumin and body mass index (BMI), exist at the time of colorectal cancer diagnosis between AA and nHw. METHODS: The University of Florida College of Medicine-Jacksonville endoscopy database was reviewed for all patients with a biopsied colorectal mass between January 2000 and December 2007. Patients were excluded if histology did not reveal colorectal adenocarcinoma or albumin/BMI was unavailable. Demographic data, tumor location, serum albumin within 60 days of diagnosis, presence of diabetes along with serum HbA1c were obtained. RESULTS: During the study period, 321 patients had colorectal masses discovered and 156 met entry criteria. There was no difference between ethnic groups regarding gender distribution, tumor location, diabetes presence, or BMI. Mean albumin was significantly less in AA compared to nHw (p < 0.01). This persisted after adjustment for gender, presence/absence of diabetes, and BMI. CONCLUSIONS: Lower albumin levels in AA indicate poorer nutritional status at colorectal cancer diagnosis compared to nHw. This may contribute to the outcome disparities observed between AA and nHw. Aggressive nutritional interventions to reverse this disparity should be evaluated.

Assessment of serum proteomics to detect large colon adenomas.

A noninvasive blood test that could reliably detect early colorectal cancer or large adenomas would provide an important advance in colon cancer screening. The purpose of this study was to determine whether a serum proteomics assay could discriminate between persons with and without a large (> or =1 cm) colon adenoma. To avoid problems of "bias" that have affected many studies about molecular markers for diagnosis, specimens were obtained from a previously conducted study of colorectal cancer etiology in which bloods had been collected before the presence or absence of neoplasm had been determined by colonoscopy, helping to assure that biases related to differences in sample collection and handling would be avoided. Mass spectra of 65 unblinded serum samples were acquired using a nanoelectrospray ionization source on a QSTAR-XL mass spectrometer. Classification patterns were developed using the ProteomeQuest algorithm, performing measurements twice on each specimen, and then applied to a blinded validation set of 70 specimens. After removing 33 specimens that had discordant results, the "test group" comprised 37 specimens that had never been used in training. Although in the primary analysis, no discrimination was found, a single post hoc analysis, done after hemolyzed specimens had been removed, showed a sensitivity of 78%, a specificity of 53%, and an accuracy of 63% (95% confidence interval, 53-72%). The results of this study, although preliminary, suggest that further study of serum proteomics, in a larger number of appropriate specimens, could be useful. They also highlight the importance of understanding sources of "noise" and "bias" in studies of proteomics assays.

Serial assessment of human tumor burdens in mice by the analysis of circulating DNA.

Internal human xenografts provide valuable animal models to study the microenvironments and metastatic processes occurring in human cancers. However, the use of such models is hampered by the logistical difficulties of reproducibly and simply assessing tumor burden. We developed a high-sensitivity assay for quantifying human DNA in small volumes of mouse plasma, enabling in-life monitoring of systemic tumor burden. Growth kinetics analyses of various xenograft models showed the utility of circulating human DNA as a biomarker. We found that human DNA concentration reproducibly increased with disease progression and decreased after successful therapeutic intervention. A marked, transient spike in circulating human tumor DNA occurred immediately after cytotoxic therapy or surgery. This simple assay may find broad utility in target validation studies and preclinical drug development programs.

[Assessment of immunotoxicity of irinotecan determined by the novel method, by which productivity of TNF-alpha from whole blood is stimulated by lipopolysaccharide].

Irinotecan hydrochloride shows much different responses in each patient, and it has severe adverse effects. Therefore, a sensitive marker for the side effect of irinotecan on immunotoxicity may be able to prevent the severe complications by the early detection. We have recently developed a method to assess the immunotoxicity by measuring the productivity of TNF-alpha from whole blood containing monocytes when stimulated by lipopolysaccharide. By using this method, the effects of continuous low-dose irinotecan therapy on immunotoxicity were assessed in 10 patients with advanced gastric or colon cancer. When compared this method with the others such as white blood cell count, lymphocyte blastoid transformation by phytohem agglutinin (PHA), and natural killer cell activity in terms of the sensitivity, immunotoxicity by this method was found earlier than the other methods. Because our original method is easy to perform and sensitive as compared to the conventional methods, it can be widely used as one of the laboratory tests useful for patients treated with immunosuppressive agents.

Vascular endothelial growth factor assessment in different blood fractions of gastrointestinal cancer patients and healthy controls.

Vascular endothelial growth factor (VEGF) is known to play a central role in tumour angiogenesis. Up to now inconclusive data have been published on the clinical-biological significance of circulating VEGF and on the most suitable blood fraction for measuring it. The aims of this pilot study were to assess VEGF in blood compartments of 16 healthy control volunteers and 56 gastrointestinal cancer patients, prospectively collected, to identify the most suitable blood fraction for the determination of VEGF and to evaluate its possible clinical-biological significance. Samples of serum (S) and plasma (P) in both sodium citrate (SC) and sodium citrate-theophylline-adenosine-dipyridamole (CTAD) were collected from venous blood. After the centrifugation and separation methods VEGF levels were detected by ELISA in: S, plasma-platelets poor (P-PP), plasma-activated platelets rich (P-APR) and blood-lysed whole (B-LW). The best differentiation between healthy control volunteers and cancer patients in VEGF level was seen for P-APRCTAD (mean value: 278 pg/ml vs 77 pg/ml; p=0.0036 by t-test). No significant correlation among the blood fractions of VEGF analysed and clinical-pathological features was found. Our data suggest that P-APRCTAD blood fraction, obtained according to well standardised conditions, could represent the most suitable compartment for the assessment of VEGF. We suggest that VEGF levels in P-APRCTAD could play a role as an angiogenic marker of malignant gastrointestinal transformation. Further studies on a larger series of patients and healthy controls with the same experimental methodological conditions are required to confirm our preliminary conclusions.

Utility of routine postoperative laboratory studies in patients undergoing potentially curative resection for adenocarcinoma of the colon and rectum.

In an effort to lower healthcare costs, this study was undertaken to evaluate the utility of routine postoperative (PO) laboratory studies and determine whether abnormalities alter patient (PT) care. This was a retrospective review of 105 PTs undergoing elective curative resection for colorectal cancer. A serum electrolyte and liver panel and a hematologic panel were drawn in all PTs. OF 8749 total laboratory values obtained, 5894 (67%) were normal. Two of these (0.03%) elicited a therapeutic intervention. Of the 2004 values that were low (23%), 103 (5.1%) elicited a therapeutic response. Of the 851 that were high (10%), 21 (2.5%) elicited a therapeutic response. Of 2089 preoperative laboratory values, 252 (12%) were abnormal, but in only 15 incidences in 9 PTs was any action taken. Three PTs required potassium supplementation and 6 PTs were transfused packed red blood cells before surgery. In the PO period 2603 laboratory values of 6660 obtained (39%) were abnormal. Of these, 735 (28%) were high and 1868 (72%) were low. Twenty of 735 (27%) high values triggered a therapeutic response that most commonly required administration of insulin for elevated serum glucose in 17 of 197 occasions in five diabetic PTs. On three occasions potassium was removed from intravenous fluids. Five of 275 (1.8%) low calcium values were treated in five patients. Potassium was replaced in 17 of 32 occasions in 14 patients where it was low. In this group of PTs, PO serum potassium, hemoglobin levels, and serum glucose in diabetics were the only values important in making therapeutic decisions. If laboratory studies can be streamlined into only those necessary, substantial savings in health care will be seen without sacrificing quality medical care.

An assessment of monocyte procoagulant activity in patients with solid tumors.

Generation of thromboplastin by monocytes has been shown to play a vital role in hypercoagulable states seen in malignancy. The purpose of this study was to compare the procoagulant activity in cancer patients and controls. Recalcification times (RT) of whole blood from 19 normal volunteers, 8 patients with benign polyps, 12 patients previously treated by surgery for head and neck (H&N) or colon cancer, and 13 untreated patients with various stages of H&N or colon cancer were determined. Tests were performed with and without stimulation with Escherichia coli endotoxin. The mean RT in saline (RTS) of untreated patients with early cancer (4.58 +/- 0.83 min) and that of patients with advanced cancer (5.23 +/- 1.16 min) were lower than that of controls (6.55 +/- 0.82 min), P less than 0.01 and P less than 0.05, respectively. The RTS of patients previously treated and of those with benign polyps were no different from those of controls. Activation with endotoxin significantly lowered the recalcification times (RTE) in the early (3.90 +/- 0.58 min) and advanced cancer patients (4.23 +/- 0.66 min) compared to the RTE of controls (5.69 +/- 0.75 min, P less than 0.01 for both groups) as well as compared to those with benign tumors, P less than 0.05. The mean RTE of previously treated patients (4.72 +/- 0.58 min) was also lower than that of controls, P less than 0.05. Our results suggest that RT is significantly reduced in cancer patients compared to that of controls. Furthermore, monocyte activation with endotoxin may enable us to distinguish cancer patients from controls as well as from those with benign tumors.

A prospective study of current diagnostic procedures for assessment of hepatic metastases in colorectal cancers.

In a prospective study of 305 patients with colorectal cancers, we assessed the diagnostic value of ultrasonography and laboratory tests. In each case laparotomy was carried out and the presence of liver metastases was established in 47 patients. The results show that the laboratory tests alone are not sufficiently accurate to detect liver metastases. Additional accuracy can be obtained by the combined use of a single liver imaging test (echography) and selected laboratory tests (C.E.A., gamma GT, Alkaline Phosphatase).