MedicalResearch.com Interview with:
Christine Veenstra MD
Clinical Lecturer, Internal Medicine
Medical Oncology
University of Michigan
Ann Arbor, MI 48109-5343
MedicalResearch: What is the background for this study? What are the main findings?Dr. Veenstra: Patients with cancer face many costs and incur financial burden as they go through diagnosis and treatment. For working patients, cancer diagnosis and treatment may come with the additional burden of time away from work, lost income, and even long-term job loss. Although 40% of US workers do not have access to paid sick leave, we hypothesized that availability of paid sick leave could reduce the need to take unpaid time away from work during cancer treatment and might therefore be associated with job retention and reduced personal financial burden.
In a survey of over 1300 patients with Stage III colorectal cancer, we found that only 55% of those who were employed at the time of their cancer diagnosis retained their jobs. Working patients with paid sick leave were nearly twice as likely to retain their jobs compared with working patients who did not have paid sick leave. This held true even when controlling for income, education and health insurance. Furthermore, working patients without paid sick reported significantly higher personal financial burden than those who had paid sick leave available.
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MedicalResearch.com Interview with:
Dr Franco Radaelli
Division of Digestive Endoscopy and Gastroenterology
Valduce Hospital
Como, ItalyMedical Research: What is the background for this study?
Dr. Radaelli: Split regimens of bowel preparation are strongly recommended by European and American Guidelines as they have been associated with a higher level of colon cleansing. However, there is still uncertainty on whether the higher level of cleansing associated with a split regimen also results in a higher proportion of subjects with at least one adenoma (adenoma detection rate, ADR), that represents by far a more relevant quality indicator than the level of cleansing itself.
On this background, we designed a randomized investigator-blinded controlled trial to evaluate whether a “split regimen” of low-volume 2-L PEG-ascorbate solution was superior to the traditional “full dose, the day before regimen” in terms of ADR. Differently from other studies on bowel preparation, we considered adenoma detection rate instead of the level of colon cleansing, the primary study end-point, and we designed the sample size accordingly. A precise estimation of the sample size was facilitated by including an homogeneous population of asymptomatic subjects undergoing first colonoscopy after positive-FIT within CRC organized screening program. Besides, ADR represents a very solid end-point due to the very low inter-pathology variability in the differential diagnosis between neoplastic and non-neoplastic lesions, while the assessment of the level of cleansing is hampered by unavoidable degree of subjectivity and higher degree of inter-operator variability.
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MedicalResearch.com Interview with: Johannes Govaert MD
Department of Surgery
Leiden University Medical Center
Leiden, The Netherlands
Medical Research: What is the background for this study?
Dr. Govaert: The Value Based Health Care agenda ofPprof. Porter (Harvard Business School) suggests that focus in healthcare should shift from reducing costs to improving quality: where quality of healthcare improves, cost reduction will follow. One of the cornerstones of potential cost reduction, as mentioned by Porter, could be availability of key clinical data on processes and outcomes of care. Despite the important societal and economical role the healthcare system fulfils, it still lags behind when it comes to standardised reporting processes. With the introduction of the Dutch Surgical Colorectal Audit (DSCA) in 2009, robust quality information became available enabling monitoring, evaluation and improvement of surgical colorectal cancer care in the Netherlands. Since the introduction of the DSCA postoperative morbidity and mortality declined.
Primary aim of this study was to investigate whether improving quality of surgical colorectal cancer care, by using a national quality improvement initiative, leads to a reduction of hospital costs. Detailed clinical data was obtained from the 2010-2012 population-based Dutch Surgical Colorectal Audit. Costs at patient-level were measured uniformly in all 29 participating hospitals and based on Time-Driven Activity-Based Costing.
Medical Research: What are the main findings?
Dr. Govaert: Over three consecutive years (2010-2012) severe complications and mortality after colorectal cancer surgery respectively declined with 20% and 29%. Simultaneously, costs during primary admission decreased with 9% without increase in costs within the first 90 days after discharge. Moreover, an inverse relationship (at hospital level) between severe complication rate and hospital costs was identified among the 29 participating hospitals. Hospitals with increasing severe complication rates (between 2010 and 2012) were associated with increasing costs whereas hospitals with declining severe complication rates were associated with cost reduction.
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MedicalResearch.com Interview with: Hannah K. Weir, PhD, MSc
Senior Epidemiologist
CDC
Medical Research: What is the background for this study? What are the main findings?
Dr. Weir: Colorectal cancer (CRC) is one of the leading causes of cancer related deaths in the United States.
We know that the risk of dying from colorectal cancer is not the same across all communities – people living in poorer communities have a higher risk of dying from colorectal cancer than people living in wealthier, better educated communities.
In this study, we estimated the number of potentially avoidable CRC deaths between 2008 and 2012 in poorer communities. Then we estimated the value of lost productivity that resulted from these deaths. Lost productivity includes the value of future lost salaries, wages, and the value to household activities such as cooking, cleaning, and child care.
We focused on the age group 50 to 74 years because this is the age group where routine CRC screening is recommended. We estimated that more than 14,000 CRC deaths in poorer communities could have been avoided and that these CRC deaths resulted in a nearly $6.5 billion dollars loss in productivity.
This is tragic - for the person who died, their family and for their community. This loss in productivity contributes to the economic burden of these already disadvantaged communities.
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MedicalResearch.com Interview with:
Van K. Morris, M.D.
Assistant Professor, GI Medical Oncology
University of Texas – M.D. Anderson Cancer Center
Houston, TX 77030Medical Research: What is the background for this study? What are the main findings?
Dr. Van K Morris: BRAF V600E mutations are associated with poor clinical outcomes for patients with metastatic colorectal cancer. Patients were enrolled in a phase I clinical trial with the BRAF inhibitor vemurafenib, the anti-EGFR antibody cetuximab, and irinotecan. Blood samples were collected every two weeks with each dose, and plasma was analyzed for changes in the fraction of mutant BRAF V600E allele relative to wild-type BRAF allele with time. Trends in circulating free DNA (cfDNA) changes were compared with radiographic changes by RECIST 1.1 criteria to examine this technique as a marker for response to therapy.
For patients who had a response radiographically, drastic reductions in the BRAF V600E allele fraction were observed even after two weeks of starting therapy, well before the first restaging scan. Patients who did not have responses radiographically had less dramatic changes relative to baseline in the BRAF V600E allele fraction. This technique analyzing cfDNA from plasma was validated using two different approaches – digital droplet PCR and next-generation sequencing by Guardant Health. Sequencing of cfDNA was also compared in pretreatment and post-progression samples, and novel mutations in MEK1 and GNAS were observed uniquely in post-progression samples.
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MedicalResearch.com Interview with:
Hans F.A. Vasen, MD
Department of Gastroenterology
Leiden University Medical Center and
Netherlands Foundation for the Detection of Hereditary Tumours
Leiden, the Netherlands
Medical Research: What is the background for this study?
Dr. Vasen: People with familial colorectal cancer (CRC) have a 3-6 fold increased risk of
colorectal cancer. It has been estimated that about 2% of the population have familial CRC (about 2.7 million people in the US). Previous studies showed that colonoscopic surveillance reduces the CRC-mortality by >80%. In people with hereditary CRC, i.e., Lynch syndrome (10 fold increased risk of CRC), an intensive screening program with colonoscopy 1x/1-2 years, is recommended. In familialcolorectal cancer, the optimal screening program is unknown.
Medical Research: What are the main findings?
Dr. Vasen: In this randomized trial with 528 individuals at risk for familial CRC, we compared screening intervals of 3 and 6 years. We found that patients had significant more high-risk adenomas (precursor lesions of CRC) at 6-years-follow-up compared to at 3-years-follow-up. However, because of the relatively low rate of high-risk adenomas at 6 years (7%) and the absence of colorectal cancer in the 6-years group, we consider a 6-year-interval safe.
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MedicalResearch.com Interview with:
Elizabeth Broussard, MD
Clinical Assistant Professor
Division of Gastroenterology
Harborview Medical Center
Seattle, WA 98105
Medical Research: What is the background for this study? What are the main findings?
Dr. Broussard: I am a clinical assistant professor of gastroenterology and I practice and teach fellows and residents GI at a safety-net hospital in Seattle and I was seeing too many late stage colorectal cancer (CRC) in our patient population. CRC is preventable with screening, and I wanted to see how the primary care clinics were performing in getting patients screened. When I looked at the baseline percentages, I realized this was an opportunity for improvement. I teamed up with an internal medicine resident Kara Walter, and we did a deep dive into the process of screening. The results of the poster presentation are a product of this teamwork, with cooperation and input from the directors of the six primary care clinics at our hospital. The main findings are that performing the FIT test is complicated and tricky for some patients, that this process can be streamlined with providing a toilet hat, a prepaid postage envelope, and improved and visual instructions. After one year, we saw statistically significant increases in overall screening with FIT in our patient population.
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MedicalResearch.com Interview with:
Harry H. Yoon, MD
Mayo Clinic
Rochester, MN 55905
Medical Research: What is the background for this study? What are the main findings?
Dr. Yoon: In the U.S., the survival of patients with colon cancer is known to differ by race, with individuals of black race having worse outcomes than those of white race.
However, it has been difficult to tease apart why the differences in survival exist.
It is generally believed that social or other non-biologic factors (eg, decreased access to care, suboptimal treatment) contribute to the discrepancy. It’s also known that differences in the general medical condition of patients could affect how long a patient lives.
However, it is unknown whether there are race-based differences in the biology of colon tumors themselves. This biology can be reflected in the genetic composition of tumors, as well as by whether and how quickly the cancer returns after the patient has undergone surgery and chemotherapy.
In addition, it is unknown whether race-based differences in biology may be related to the age of the patient at the time of diagnosis. Blacks with colorectal cancer typically have an earlier age of onset than whites do.
A major barrier to addressing these questions are that there are very few large populations of colon cancer patients where everyone had the same disease stage and received uniform treatment, and where patients were monitored for years afterward specifically to see whether the cancer returned. It is much harder to measure whether cancer has returned (ie, cancer recurrence), as compared to simply knowing whether a patient is alive or dead. This difference is important, because knowing about cancer recurrence sheds more light on cancer biology than only knowing about patient survival, since many factors unrelated to cancer biology (eg., heart disease) can affect whether a person is alive or dead.
The most reliable data on cancer recurrence (not just patient survival) generally comes from patients who have enrolled in a clinical trial. In the Alliance N0147 trial, all patients had the same cancer stage (ie, stage III), underwent surgery and received standard of care chemotherapy (ie, “FOLFOX”) after surgery. Patients had uniform, periodic monitoring after chemotherapy to see if the cancer returned.
In other words, examining racial outcomes in this cohort largely eliminates some of the key factors (eg, decreased access to care, suboptimal treatment) that are believed to contribute to racial discrepancies, and provides a unique opportunity to determine if differences in cancer biology between races may exist.
This study was done to see if colon cancers are genetically different based on race, and whether race-based differences exist in cancer recurrence rates.
The study found that tumors from whites, blacks, and Asians were different in terms of the frequency of mutations in two key cancer-related genes, BRAF and KRAS. Tumors from whites were twice as likely to have mutated BRAF (14% in whites compared to 6% in Asians and 6% in blacks). Tumors from blacks had the highest frequency of KRAS mutations (44% in blacks compared to 28% in Asians and 35% in whites). Tumors from Asians were the mostly likely to have normal copies of both genes (67% in Asians compared to 50% in blacks and 51% in whites).
Next, the study found that the colon cancers among blacks had more than double the risk of cancer recurrence, compared to whites. However, this discrepancy was only evident among young patients (ie, aged less than 50 years). Almost 50% of younger black patients experienced colon cancer recurrence within 5 years, compared to ~30% of black patients over age 50, or compared to white or Asian patients regardless of age. The worse outcome among young blacks remained evident even after adjusting for many potential confounding factors, such as tumor grade, the number of malignant nodes, or the presence of BRAF or KRASmutations. Because this question was examined in a clinical trial cohort of uniform stage and treatment, the role of multiple important potential confounders was diminished.
To our knowledge, this is the first report indicating that colon cancers from young black individuals have a higher chance of relapsing after surgery and chemotherapy, compared to those from white individuals.
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MedicalResearch.com Interview with:
Ahmad M. Khalil, PhD
Department of Genetics
School of Medicine
Case Western Reserve University
Cleveland, Ohio 44106-4955
Medical Research: What is the background for this study? What are the main findings?
Dr. Khalil: DNA in human cells is modified chemically by methylation. The process of DNA methylation plays important roles in protecting human DNA and ensures proper gene expression. In cancer cells, the process of DNA methylation becomes deregulated, however, the mechanisms of how this occurs are not known. In our study, we have uncovered a novel mechanism on how colon cancer cells change their DNA methylation, and consequently, become more tumorigenic. We specifically identified a long non-coding RNA that interacts with and regulates the enzyme that modifies DNA with methylation - the enzyme is called DNMT1. This lncRNA become suppressed in colon tumors, which we believe is a key step in loss of DNA methylation in colon cancer cells.
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MedicalResearch.com Interview with:
Søren Friis, Senior Scientist, Associate Professor, MD
Danish Cancer Society Research Center
Danish Cancer Society
Department of Public Health
University of Copenhagen
Faculty of Health Institute of Clinical Medicine
Department of Clinical Epidemiology
Aarhus University Denmark
Medical Research: What is the background for this study? Dr. Friis: Although laboratory, clinical, and epidemiological studies have all provided strong evidence for protection against colorectal cancer from regular use of aspirin, the optimal dose and duration of use for cancer prevention remain to be established.
Medical Research: What are the main findings?
Dr. Friis: Continuous use of low-dose aspirin for five or more years was associated with a reduced risk of colorectal cancer, but overall long-term use (continuous or non-continuous) was not. Long-term, high-intensity use (average of ≥0.3 daily doses) of non-aspirin NSAIDs was associated with a substantially reduced risk of colorectal cancer, particularly for NSAIDs with the highest COX-2 selectivity.
The results for long-term continuous users of low-dose aspirin should be interpreted cautiously, since these patients comprised only a small proportion of the low-dose aspirin users and might have a risk profile different from that of the general population.
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MedicalResearch.com Interview with:
Dr Andrew Kunzmann & Dr Helen Coleman
Joint first authorsCentre for Public Health
Queen’s University Belfast
Northern Ireland
Medical Research: What is the background for this study?
Response: There is now a large amount of evidence to suggest that individuals who consume diets high in fiber tend to be at a lower risk of bowel (colorectal) cancer. However, it is not known whether this association begins at the early stages of bowel cancer development or at later stages, in individuals with polyps (adenomas) that can lead to bowel cancer if left untreated. The best source of dietary fiber (cereals, fruit or vegetables) for bowel adenoma and cancer prevention is also debatable.
We analysed data from individuals taking part in a large U.S trial assessing bowel screening, who completed a dietary questionnaire and received sigmoidoscopy screening at the start of the trial and received further screening 3 to 5 years later. This allowed us to investigate whether individuals with higher fiber diets had a lower risk of developing their first left-sided adenoma, but also for having adenomas recur at a later time, or indeed risk of bowel cancer, than individuals with diets low in fiber. By analysing only the screened participants, everyone had an equal opportunity to have their recurrent adenomas diagnosed – something that previous studies of dietary fiber have been unable to address.
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MedicalResearch.com Interview with:
S. Yousuf Zafar, MD, MHS
Associate Professor of Medicine
Duke Cancer Institute
Duke Clinical Research Institute
Medical Research: What is the background for this study? What are the main findings?
Dr. Zafar: Multiple studies have suggested that obesity and colorectal cancer are related. For instance, obesity has been linked with an increased incidence of colon cancer. Obesity has also been associated with a greater risk of colon cancer recurrence. To date, no study has looked at the role of obesity in outcomes for patients with metastatic colorectal cancer. In our study of over 6000 patients receiving treatment for metastatic olcolorectal cancer, we found that patients with the lowest body mass index (BMI) were at greatest risk for worse survival. This does not mean that obesity is good. More likely, it means that those who are very underweight are least able to tolerate the best treatment, or being very underweight is a biologic marker of poor prognosis.
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MedicalResearch.com Interview with:
Dr. Hannah Arem Ph.D. M.H.S. Postdoctoral Fellow
Nutritional Epidemiology Branch
Division Cancer Epidemiology and Genetics
National Cancer Institute
MedicalResearch: What is the...
MedicalResearch.com Interview with:
Howard S. Hochster, MD
Associate Director, Yale Cancer Center
Professor of Medicine, Yale School of Medicine
New Haven, CT 06520
Medical Research: What is the background for this study? What are the main findings?
Dr. Hochster: TAS-102 is a novel anti-metabolite, recently combined with a metabolic inhibitor to make it orally bioavailable and active in the treatment of cancer. In pre-clinical studies, it is non-cross reactive with 5FU. What this means practically is that we have another chemotherapy agent that can be used for patients with colon cancer. This drug will be an addition to the approved chemotherapy agents 5FU, oxaliplatin and irinotecan. It may be combinable with these and with targeted agents to provide new active regimens.
The main findings of the study were published in NEJM, May 15, 2015. The study enrolled 800 patients randomized (2:1 ratio) to drug vs placebo. Patients with advanced colon cancer who had been treated with all the previously approved drugs were eligible. The drug was active in reducing time to tumor growth (Progression Free Survival) by 50% and improved overall survival for treated patients by about 25%.
The data I presented at ESMO included a further analysis on specific genomic subsets of patients within the 800 patient study. All patients were tested locally for RAS mutations and about 50% had such mutations (as expected). There was no differences in benefit or toxicity for those with RAS wild-type tumors or RAS mutated tumors. We also looked at those with BRAF mutations, but only 15% of patients were tested and this mutation occurs in about 8% of colon cancer, so we had very few patients with BRAF mutation. Given this limitation, it appeared that this did not make a difference for benefit or toxicity either.
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MedicalResearch.com Interview with:
Michael B. Burns, Ph.D.
HHMI Post-Doctoral Fellow
Dept. of Genetics, Cell Biology and Development
Dept. of Ecology, Evolution, and Behavior
Masonic Cancer Center
Dept. of Biology Teaching and Learning
University of Minnesota Twin Cities
St. Paul, MN 55108
Medical Research: What is the background for this study?
Dr. Burns: Recent technological advances have made it possible to survey all the of microbes that are in, on, and around us. One of the surprising things is the sheer quantity and diversity of the bacteria in our environments and our microbiomes. Many researchers have begun the systematic characterization of the microbes that are associated with specific disease states, including cancer. With regard to colorectal cancer, there have been numerous studies that have identified specific bacteria that are linked to the presence of the disease. There have been many reports that have identified particular potentially important microbes that may be causing the cancer, driving the cancer, or some combination of the two. Among these microbes, one of the best studied so far is a group of bacteria called Fusobacterium.
Medical Research: What are the main findings?
Dr. Burns: In our work, we set out to perform another characterization of the bacteria in the gut microbiome that are specifically associated with colorectal tumors. We used samples of normal colon tissue from the same individuals as controls, which allowed us to account for much of the variability in the different bacteria we found that might have been simply the result of, for instance, diet. In our analysis, we confirmed the previous results related to Fusobacterium, and additionally discovered a new potential culprit in colorectal cancer, a group of bacteria named Providencia.
The finding of another new set of microbes that might be causing or driving cancer is not surprising. As indicated above, there are many groups who have found other potential candidate microbes that could be implicated in the disease. Our next question was to determine if there was some reason why there might be so many different bacteria that are linked with the disease and what it might be able to tell us about what these bacteria are doing. To that end, we used computational approaches to assess what these two groups of bacteria might be doing at a functional level and if there were any similarities. We found that there was a great deal in common between Fusobacterium and Providencia, including a finding that one of the common functions was related to a large group of virulence genes.
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MedicalResearch.com Interview with:
Prof. Catherine Quantin
Teaching Hospital, Department of Biostatistics and Medical Informatics France;
Dijon University Hospital, Clinical Investigation Center,
Clinical Epidemiology/Clinical Trials Unit, Dijon, France and
Dr Michal Abrahamowicz Ph.D
Department of Epidemiology, Biostatistics and Occupational Health
McGill University, Montreal, Canada
Medical Research: What is the background for this study? Response: One difficulty, common to prognostic studies of cancer, concerns the need to separate the effects of prognostic factors on different clinical endpoints, such as disease recurrence vs recurrence-free death. Some published prognostic studies used a Cox regression model that included recurrence as a time-dependent covariate, to assess the impact of recurrence on mortality, and to adjust for recurrence when estimating the effects of other prognostic factors on mortality. However, the Cox model is limited to the assessment of the effects of covariates on a single endpoint, such as death. This limitation is overcome by multi-state models, that make it possible to model alternative pathways of disease progression and to assess the impact of prognostic factors on both recurrence-free death vs death after recurrence, and recurrence followed by death.
Another difficulty, is that the cause of death is not available or not accurately coded. Yet, some patients are likely to die of causes not related to the disease of primary interest, especially in cancers with longer survival and in those that affect older subjects. The effects of prognostic factors estimated with Cox model, or classic multi-state models, are not able to discriminate between their effects on the mortality due to cancer of primary interest vs natural mortality. However, age is a very strong predictor of overall mortality, but is not systematically associated with higher cancer-specific mortality.
To deal with this difficulty, many prognostic studies use relative survival methods.
The general idea is to use the mortality tables for the relevant general population to estimate survival corrected for the expected natural mortality, due to other causes of death. (more…)
MedicalResearch.com Interview with: Timothy Michael Pawlik, M.D., M.P.H., Ph.D.
Chief, Division of Surgical Oncology
Professor of Surgery
John Hopkins
Medical Research: What is the background for this study?
Dr. Pawlik: The prognosis of patients operated on for colorectal liver metastasis (CRLM) is currently defined by various “traditional” clinicopathologic factors. However the insight that they provide is incomplete. KRAS is the most common oncogene of the RAS family and is reported in up to 30 to 40% of patients with colorectal liver metastasis. As a result, KRAS mutational status recently attracted a lot of attention as a potential prognostic factor in colorectal liver metastasis. However, overall mutant KRAS status (compared to wild type) correlated with worse survival only in some studies.
We hypothesized that the specific KRAS activating mutations (codon 12 and codon 13) confer different biologic behaviors to the tumor and in turn, account for different (if any) prognostic values. The different proportions of each KRAS specific mutation could determine whether the overall mutational status would be associated with worse survival. In our view, the different proportions of specific mutations in various cohorts could account for the variability of the outcomes in different studies.
Medical Research: What are the main findings?
Dr. Pawlik: Our results showed that only codon 12 KRAS mutations conferred a worse prognosis whereas codon 13 ones did not. Furthermore, we examined the different point mutations that constitute codon 12 mutations and we found that among G12A, G12D, G12V, G12C and G12S KRAS point mutations, only G12V and G12S were independent prognostic factors of worse survival. That confirmed our hypothesis that only some of the point mutations do have a significant prognostic role and that the relative incidence of those mutations could determine if overall KRAS mutational status would be associated with worse survival in a certain cohort. (more…)
MedicalResearch.com Interview with:
Aaron P. Thrift, Ph.D.
Assistant Professor, Department of Medicine
Dan L. Duncan Cancer Center
Baylor College of Medicine
Houston, TX 77030-3498
Medical Research: What is the background for this study? What are the main findings?
Dr. Thrift: Greater attained adult height is associated with increased risk of all cancers combined; however, the association may differ by cancer site and between women and men. For colorectal cancer, epidemiological studies suggest that the association with height may be stronger for women than for men. We used data from over 10,000 patients with colorectal cancer and over 10,000 population-based controls and conducted multiple analyses, including using Mendelian randomization (which incorporates genomic data with traditional approaches) to overcome potential issues of confounding and bias in observational studies, to further examine the association between height and risk of colorectal cancer. Overall, we found that taller height was associated with increased risk of colorectal cancer (8% increased risk per 10cm increase in height). When we examined women and men separately, our results strongly suggest that height is causally associated with colorectal cancer risk for women, whereas there was weaker evidence for a causal association between height and colorectal cancer risk for men.
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MedicalResearch.com Interview with:
Dr. Jeanne Tie
Medical Oncologist | Royal Melbourne and Western Hospital
Research Fellow
Walter and Eliza Hall Institute of Medical Research
Parkville, VIC
Medical Research: What is the background for this study?
Dr. Tie: The increasing number of active agents available to treat metastatic colorectal cancer has resulted in an ever-improving life expectancy in this group of patients. However, the ability to expose patients with metastatic colorectal cancer to all effective anti-cancer treatment, particularly 3rd line treatment and beyond, is increasingly challenging in routine practice as some patients’ condition deteriorate too rapidly and do not live long enough to enjoy the benefit of these additional therapies. This is partly due to the current imaged-based method of assessing treatment response with the Response Evaluation Criteria in Solid Tumors (RECIST), which is usually performed every 8-12 weeks during the course of treatment. This means that for non-responders to treatment, several weeks to months will elapse before a switch to alternative therapy will be made. Conceptually, if a patient’s response to treatment could be made earlier, such as with a blood test, then an earlier switch to an alternative treatment can be made, minimizing the side-effects of the ineffective therapy and providing the opportunity for a more effective one. Currently, blood biomarkers add little to imaging-based assessment, with CEA lacking sensitivity and specificity.
Colorectal cancer is characterised by several recurrently mutated genes and advances in genomics and molecular technologies have now enabled rapid detection and quantification of these cancer-specific mutations in patient’s circulation (circulating tumor DNA - ctDNA). Previous studies have demonstrated that ctDNA can be detected in a high proportion of patients with advanced cancer. In this study, we describe the potential role of ctDNA as an early predictor of treatment response in patients with treatment naïve metastatic colorectal cancer (mCRC) undergoing chemotherapy and as a marker of disease bulk that could complement RECIST measurement. (more…)
MedicalResearch.com Interview with:
Dr. H. Jaap Bonjer, PhD, FRCSC
Professor of Surgery
Chair Department of Surgery
VU University Medical Center Amsterdam
Amsterdam
Medical Research: What is...
MedicalResearch.com Interview with:
Professor Massimiliano Mazzone and Professor Hans Prenen
Lab of Molecular Oncology and Angiogenesis
VIB Vesalius Research Center
University of Leuven Leuven Belgium
Medical Research: What is the background for this study? What are the main findings?
Response: Monocytes are circulating cells with patrolling behaviour. In case of harmful situations, they go to the site of injury rapidly to ensure immune and wound-healing functions. Once in the inflammation site, they differentiate into macrophages which are versatile cells adopting different phenotypes according to the stimuli they are subjected to. We hypothesized that cancer cells might release signals and soluble factors that educate and change monocytes already when in circulation. In this work, we proved our hypothesis and found that soluble molecules released by colorectal cancer cells imprint a specific signature in the circulating monocytes. Now, by collecting these monocytic cells from the blood, we are able to determine if colorectal cancer cells are present in the body, either at the primary site (in the colon) or in distant organs (where cancer cells give rise to metastases). (M. Mazzone).
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MedicalResearch.com Interview with:
Matthew B. Yurgelun, MD
Instructor in Medicine
Harvard Medical School
Medical Research: What is the background for this study? What are the main findings?
Dr. Yurgelun: Germline mutations in the TP53 gene are linked to Li-Fraumeni syndrome, which is an inherited syndrome associated with a 73-100% lifetime risk of cancer. Classically, cancers linked to Li-Fraumeni syndrome include early-onset breast cancer, leukemias, soft tissue sarcomas, brain cancer, and adrenocortical cancer, although recent data have shown an increased risk of colorectal cancer as well. Our study’s primary aim was to determine the frequency of germline TP53 mutations in patients with early-onset colorectal cancer.
We studied 457 patients from the multinational Colon Cancer Family Registry who were diagnosed with colorectal cancer at age 40 or younger, and found that 1.3% carried a germline alteration in the TP53 gene. None of these individuals had personal or family histories of cancer that fulfilled clinical criteria for Li-Fraumeni syndrome. (more…)
MedicalResearch.com Interview with:
Michael J. Orlich, MD, PhD
Program Director, Preventive Medicine Residency
Loma Linda University
Co-Investigator, Adventist Health Studies
Medical Research: What is the background for this study? What are the main findings?Dr. Orlich: Colorectal cancer is the second leading cause of death from cancer in the United States. Screening efforts such as colonoscopies have helped save many lives by detecting pre-cancerous polyps and removing them. However, it is even better to prevent cancers from forming in the first place. We call this primary prevention. Diet is a potentially important approach to reduce the risk of developing colorectal cancer. In this analysis, we compared those eating different categories of vegetarian dietary patterns to those eating a non-vegetarian diet. About half of our study population was classified as non-vegetarian, which we defined as eating meat at least weekly. The other half of our population we called vegetarian and further divided them into four different vegetarian groups: semi-vegetarians ate meat but less than once per week; pesco-vegetarians ate fish but avoided other meats; lacto-ovo-vegetarians avoided meat but ate eggs and/or dairy products; and vegans avoided all meats, eggs, and dairy. All vegetarians together had on average a 22% relative reduction in the risk of developing colorectal cancer, compared to non-vegetarians, after carefully adjusting for many other factors. Pesco-vegetarians in particular had a much lower risk compared to non-vegetarians. (more…)
MedicalResearch.com Interview with:
Kim F. Rhoads, MD, MS, MPH, FACS
Assistant Professor of Surgery
Director, Community Partnership Program
Stanford Cancer Institute Unit Based Medical Director, E3 Surgery and Surgical Subspecialties Stanford University Stanford, Ca 94305
Medical Research: What is the background for this study? What are the main findings?Dr. Rhoads: Colon cancer is the 3rd most common cancer in US men and women and is the 2nd most common cause of cancer death. For at least 2 decades, minorities with colon cancer have suffered a 15-20% additional risk of death when compared with non-minority patients. Our study set out to understand the influence of the location where treatment was delivered and the quality of care received, on overall survival and racial disparities.
We examined more than 30,000 patients who were diagnosed and treated for colon cancer in California from 2001 through 2006. Using cancer registry data linked to state level inpatient data and hospital information, we compared the rates of National Comprehensive Cancer Network (NCCN) guideline adherence and mortality by location of care and by race. We found that patients treated within an integrated health system (IHS) received NCCN guideline based care at higher rates than those treated outside the system—about 3% higher rates of surgery; and more than 20% higher rates of stage appropriate chemotherapy. The rates of guideline based care were nearly equal between the racial groups treated inside the IHS. Propensity score matched comparisons revealed a lower risk of death for all patients and no racial disparities associated with treatment within the Integrated system. For patients treated outside IHS, the disparity in mortality was explained by accounting for differences in receipt of evidence based care by race.
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MedicalResearch.com Interview with:
Jason A. Zell, D.O., M.P.H.
Program Director, Hematology/Oncology Fellowship Program
Division of Hematology/Oncology
Department of Medicine UC Irvine Health
Medical Research: What is the background for this study? What are the main findings?
Dr. Zell:Colorectal cancer incidence (CRC) has been declining in the U.S. since 1975, due largely to screening for premalignant polyps. Screening in the U.S. begins at age 50 for average risk individuals, and so the vast majority of Young Adults in the U.S. (defined as age 20-39 in our study) are unscreened. Recently, several studies have reported an increased risk of colorectal cancer among U.S. individuals under age 50. In our analysis of 231,544 CRC cases in California over a 22 year period, we identified 5617 cases among Young Adults (age 20-39). As expected, the overall risk of colorectal cancer in Young Adults is low. However, colorectal cancer is increasing among Young Adults as observed in this population-based study, and certain groups remain at particularly high risk. For example, Hispanic Females age 20-29 were observed to have nearly a 16% increase in colorectal cancer risk when comparing the Biannual Percent Change over the course of the study period. Also concerning was the observation that Young Adults were more likely to be diagnosed with colorectal cancer at an advanced stage than adults in the “screened population” (ie, those age 50 and over).
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MedicalResearch.com Interview with:
Dr Siu Hing Lo
Research Associate in Health Psychology UCL
Research Department of Epidemiology and Public
Medical Research: What is the background for this study? What are the main findings?Dr. Lo: Most types of population-based cancer screening – such as the Faecal Occult Blood (FOB) test – require repeat participation to be effective. The Faecal Occult Blood test is a stool test that typically needs to be self-completed every two years. This study investigated predictors of repeat participation in the NHS Bowel Cancer Screening Programme (BCSP). Late kit return, a definitive abnormal [FOB test] result and failure to comply with a follow-up colonoscopy in a previous screening episode were consistently and independently associated with lower repeat uptake.
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MedicalResearch.com Interview with:
Jeffrey H. Silber, M.D., Ph.D.
The Nancy Abramson Wolfson Endowed Chair in Health Services Research Director, Center for Outcomes Research
The Children's Hospital of Philadelphia
Professor of Pediatrics, Anesthesiology & Critical Care
The Perelman School of Medicine
Professor of Health Care Management, The Wharton School
The University of Pennsylvania Philadelphia, PA 19104
Medical Research: What is the background for this study? What are the main findings?
Response: Differences in colon cancer survival by race is a well recognized problem among Medicare beneficiaries. We wanted to determine to what extent the racial disparity in survival is due to a racial disparity in presentation characteristics at diagnosis (such as advanced stage and the presence of chronic diseases) versus a disparity in subsequent treatment by surgeons and oncologists.
To answer this question, we compared black colon cancer patients to three matched white groups:
(1) “Demographics” match controlling age, sex, diagnosis year, and Survey, Epidemiology, and End Results (SEER) site;
(2) “Presentation” match controlling demographics plus comorbidities and tumor characteristics including stage and grade; and
(3) “Treatment” match including presentation variables plus details of surgery, radiation and chemotherapy.
We studied Medicare patients 65 years of age and older diagnosed between 1991-2005 in the SEER-Medicare database. There were 7,677 black patients and 3 sets of 7,677 matched white controls.
We found that difference in 5-year survival (black-white) was 9.9% in the demographics match. This disparity remained unchanged between 1991-2005. After matching on presentation characteristics, this difference fell to 4.9%. Finally, after additionally matching on treatment, this same difference hardly changed, moving to only 4.3%. So the disparity in survival attributed to treatment differences comprised only an absolute 0.6% of the overall 9.9% survival disparity.
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MedicalResearch.com Interview with:
Reinier G.S. Meester, M.Sc
Department of Public Health,
ErasmusMC, Rotterdam, Netherlands
Medical Research: What is the background for this study? What are the main findings?
Response: Despite decreasing death rates from colorectal cancer over the past decades, it still ranks as the second leading cause of cancer deaths in the U.S. Screening for colorectal cancer is highly effective, but only 58% of the eligible population reported up-to-date with screening. This suggests that a substantial proportion of current colorectal cancer deaths in the U.S. are avoidable.
We found that approximately 60% (32,200 deaths) of current deaths from colorectal cancer may be due to not receiving screening.
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MedicalResearch.com Interview with:
Xianglin L. Du, MB, MS, Ph.D.
Professor of Epidemiology,
Department of Epidemiology, Human Genetics, and Environmental Sciences,
The University of Texas School of Public Health,
Houston, TX 77030, USA.
Medical Research: What is the background for this study? Dr. Du: Widespread use of screening and advances in screening strategies played a key role in colorectal cancer survival improvement. With the increasing evidence on the benefit of fecal occult blood test and sigmoidoscopy during 1990s, the U.S. Preventive Service Task Force for the first time in 1996 recommended the annual use of fecal occult blood test, periodic use of sigmoidoscopy, or routine use of both modalities for all persons aged 50 or older. Because colonoscopy is able to detect lesions in the entire colon and has a high sensitivity for lesions of over 10mm in size, Medicare began to cover colonoscopy since 2001 for individuals with average-risk of colorectal cancer. Advances in chemotherapy, particularly some new therapeutic regimens approved by Food and Drug Administration (FDA) over the past decades also played a key role in survival improvement for patients with colorectal cancer. However, the overall impact of newly approved chemotherapy regimens on survival in population-based elderly patients remains unclear. It is also unknown what proportion of survival improvement was attributable to changes in tumor stage and size due to screening, and what proportion was attributable to more effective chemotherapy regimens. Hence, we studied a large nationwide and population-based cohort of elderly colorectal cancer patients to examine the changes in tumor stage and tumor size from 1992 to 2009, and to further quantify the effects of changes in stage/size and chemotherapy regimens on improved survival over the two decades.
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MedicalResearch.com Interview with: Enrique Quintero MD, PhD
President, Asociación Española de Gastroenterología (AEG)
Chief of Gastroenterology, Hospital Universitario de Canarias
Professor of Medicine, Universidad de La Laguna
La Laguna. Tenerife Spain
Medical Research: What is the background for this study? What are the main findings?Dr. Quintero: First degree relatives (FDRs) of patients with colorectal cancer (CRC) are at increased risk of developing the disease compared with the general population. For that reason, clinical practice guidelines recommend colonoscopy every five years starting at the age of 40 years or ten years less than the youngest case in the family. However, this approach has some drawbacks:
first, several studies have shown that the benefit of colonoscopy is limited by a low uptake (less than 40%);
second, it represents an important colonoscopy burden, as about 70-80% of explorations are normal or without relevant lesions, which implies a high resource consumption; and
third, this recommendation is not based on evidence, as no randomized controlled trials have compared the efficacy of screening colonoscopy with that of other strategies.On the other hand, pilot studies have shown that one-time fecal immunochemical tests (FIT) have acceptable capacity to detect advanced neoplasia (defined as cancer or advanced adenoma) in family members of patients with CRC. For these reasons we conducted a prospective randomized trial to compare the efficacy of repeated fecal immunochemical tests versus one-time colonoscopy for detecting advanced colorectal neoplasia in asymptomatic FDRs of patients with colorectal cancer.
The main finding of our study was that cumulative fecal immunochemical tests screening (1 per year, during 3 years), yielded an equivalent detection rate to one-time colonoscopy for cancer, advanced adenoma and advanced neoplasia both by intention-to-screen and per-protocol analysis, after controlling for confounders such as age, gender, index-case age, and number of affected relatives. In fact, FIT detected all cancers and 61% of advanced adenomas. In addition, the study confirmed that the number of subjects requiring colonoscopy to detect one advanced neoplasm was 4 times less in individuals screened by FIT than in those screened by colonoscopy. Therefore, FIT may save a substantial number of unnecessary colonoscopies, preventing harms and lowering costs. (more…)
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