For patients with metastatic colorectal cancer, stratification for treatment (surgery or chemotherapy) is often based on crude clinicopathological characteristics like tumour size and number of ...lesions. Circulating tumour DNA (ctDNA) acts as a potential biomarker of disease trajectory and biology, allowing better stratification.
This study aims to systematically review ctDNA in stage IV colorectal cancer to assess its potential role as a prospective biomarker to guide management decisions.
A literature search was performed to identify studies where the measurement of ctDNA in stage IV colorectal cancer was correlated with a clinical outcome (radiological response, secondary resection rate, PFS, DFS or OS).
Twenty-eight studies were included, reporting on 2823 patients. Circulating tumour DNA was detectable in between 80% and 90% of patients prior to treatment. Meta-analysis identified a strong correlation between detectable ctDNA after treatment (surgery or chemotherapy) and overall survival (HR 2.2, 95% CI 1.79–2.69, p < 0.00001), as well as progression-free survival (HR 3.15, 95% CI 2.10–4.73, p < 0.00001). ctDNA consistently offered an early marker of long-term prognosis in irresectable disease, with changes after one cycle of systemic therapy demonstrating prognostic value. In resectable disease treated with curative intent, detection of ctDNA offered a lead time over radiological recurrence of 10 months.
Circulating tumour DNA is detectable in the majority of resectable and irresectable patients. The presence of ctDNA is clearly associated with shorter overall survival, with changes in ctDNA an early biomarker of adverse disease behaviour. Prospective trials are essential to test its clinical efficacy.
•ctDNA is detectable in 80–90% of patients with mCRC.•Levels of ctDNA are strongly predictive of survival in mCRC.•Dynamic assessment of ctDNA offers an early marker of treatment efficacy.•ctDNA may offer a route to stratified treatments for mCRC.
To describe patterns of recurrence and postrecurrence survival in a large cohort of accurately staged patients with Dukes' A-C colorectal cancer.
Recurrence remains a frequent cause of mortality ...after the treatment of colorectal cancer with curative intent. Understanding the likelihood and site of recurrence informs adjuvant treatment and follow-up.
Retrospective cohort analysis of data from the FACS (follow-up after colorectal cancer surgery) trial after a median 4.4 years of follow-up; postrecurrence survival was calculated using the Kaplan-Meier method.
Complete data were available for 94% of patients; 189 (17%) patients had experienced recurrence. Incidence of recurrence varied according to the site of the primary (right colon: 51/379, 14%; left colon: 68/421, 16%; rectum: 70/332, 21%; P = 0.023) and initial stage (Dukes' A: 26/249, 10%; Dukes' B: 81/537, 15%; Dukes' C: 82/346, 24%; P < 0.0001). Pulmonary recurrence was most frequently associated with rectal tumors, and multisite/other recurrence with right-sided colonic tumors. Recurrences from lower-stage tumors were more likely to be treatable with curative intent (Dukes' A: 13/26, 50%; Dukes' B: 32/81, 40%; Dukes' C: 20/82, 24%; P = 0.03). Those with rectal tumors benefited most from follow-up (proportion with treatable recurrence: rectum 30/332, 9%; left colon 23/421, 6%; right colon 12/379, 3%; P = 0.003). Both initial stage (log rank P = 0.005) and site of primary (log rank P = 0.01) influenced postrecurrence survival.
The likelihood and site of recurrence, and survival, are influenced by the site and stage of the primary tumor. Those with rectal cancers benefited most from follow-up.ISRCTN 41458548.
To evaluate the diagnostic accuracy of a single CEA (carcinoembryonic antigen) blood test in detecting colorectal cancer recurrence.
Patients who have undergone curative resection for primary ...colorectal cancer are typically followed up with scheduled CEA testing for 5 years. Decisions to investigate further (usually by CT imaging) are based on single test results, reflecting international guidelines.
A secondary analysis was undertaken of data from the FACS trial (two arms included CEA testing). The composite reference standard applied included CT-CAP imaging, clinical assessment and colonoscopy. Accuracy in detecting recurrence was evaluated in terms of sensitivity, specificity, likelihood ratios, predictive values, time-dependent area under the ROC curves, and operational performance when used prospectively in clinical practice are reported.
Of 582 patients, 104 (17.9%) developed recurrence during the 5 year follow-up period. Applying the recommended threshold of 5μg/L achieves at best 50.0% sensitivity (95% CI: 40.1-59.9%); in prospective use in clinical practice it would lead to 56 missed recurrences (53.8%; 95% CI: 44.2-64.4%) and 89 false alarms (56.7% of 157 patients referred for investigation). Applying a lower threshold of 2.5μg/L would reduce the number of missed recurrences to 36.5% (95% CI: 26.5-46.5%) but would increase the false alarms to 84.2% (924/1097 referred). Some patients are more prone to false alarms than others-at the 5μg/L threshold, the 89 episodes of unnecessary investigation were clustered in 29 individuals.
Our results demonstrated very low sensitivity for CEA, bringing to question whether it could ever be used as an independent triage test. It is not feasible to improve the diagnostic performance of a single test result by reducing the recommended action threshold because of the workload and false alarms generated. Current national and international guidelines merit re-evaluation and options to improve performance, such as making clinical decisions on the basis of CEA trend, should be further assessed.
Intensive follow-up after surgery for colorectal cancer is common practice but lacks a firm evidence base.
To assess whether or not augmenting symptomatic follow-up in primary care with two intensive ...methods of follow-up monitoring of blood carcinoembryonic antigen (CEA) levels and scheduled imaging is effective and cost-effective in detecting the recurrence of colorectal cancer treatable surgically with curative intent.
Randomised controlled open-label trial. Participants were randomly assigned to one of four groups: (1) minimum follow-up (
= 301), (2) CEA testing only (
= 300), (3) computerised tomography (CT) only (
= 299) or (4) CEA testing and CT (
= 302). Blood CEA was measured every 3 months for 2 years and then every 6 months for 3 years; CT scans of the chest, abdomen and pelvis were performed every 6 months for 2 years and then annually for 3 years. Those in the minimum and CEA testing-only arms had a single CT scan at 12-18 months. The groups were minimised on adjuvant chemotherapy, gender and age group (three strata).
Thirty-nine NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence.
A total of 1202 participants who had undergone curative treatment for Dukes' stage A to C colorectal cancer with no residual disease. Adjuvant treatment was completed if indicated. There was no evidence of metastatic disease on axial imaging and the post-operative blood CEA level was ≤ 10 µg/l.
Surgical treatment of recurrence with curative intent.
Time to detection of recurrence, survival after treatment of recurrence, overall survival and quality-adjusted life-years (QALYs) gained.
During 5 years of scheduled follow-up, cancer recurrence was detected in 203 (16.9%) participants. The proportion of participants with recurrence surgically treated with curative intent was 6.3% (76/1202), with little difference according to Dukes' staging (stage A, 5.1%; stage B, 7.4%; stage C, 5.6%;
= 0.56). The proportion was two to three times higher in each of the three more intensive arms (7.5% overall) than in the minimum follow-up arm (2.7%) (difference 4.8%;
= 0.003). Surgical treatment of recurrence with curative intent was 2.7% (8/301) in the minimum follow-up group, 6.3% (19/300) in the CEA testing group, 9.4% (28/299) in the CT group and 7.0% (21/302) in the CEA testing and CT group. Surgical treatment of recurrence with curative intent was two to three times higher in each of the three more intensive follow-up groups than in the minimum follow-up group; adjusted odds ratios (ORs) compared with minimum follow-up were as follows: CEA testing group, OR 2.40, 95% confidence interval (CI) 1.02 to 5.65; CT group, OR 3.69, 95% CI 1.63 to 8.38; and CEA testing and CT group, OR 2.78, 95% CI 1.19 to 6.49.
A Kaplan-Meier survival analysis confirmed no significant difference between arms (log-rank
= 0.45). The baseline-adjusted Cox proportional hazards ratio comparing the minimum and intensive arms was 0.87 (95% CI 0.67 to 1.15). These CIs suggest a maximum survival benefit from intensive follow-up of 3.8%.
The incremental cost per patient treated surgically with curative intent compared with minimum follow-up was £40,131 with CEA testing, £43,392 with CT and £85,151 with CEA testing and CT. The lack of differential impact on survival resulted in little difference in QALYs saved between arms. The additional cost per QALY gained of moving from minimum follow-up to CEA testing was £25,951 and for CT was £246,107. When compared with minimum follow-up, combined CEA testing and CT was more costly and generated fewer QALYs, resulting in a negative incremental cost-effectiveness ratio (-£208,347) and a dominated policy.
Although this is the largest trial undertaken at the time of writing, it has insufficient power to assess whether or not the improvement in detecting treatable recurrence achieved by intensive follow-up leads to a reduction in overall mortality.
Rigorous staging to detect residual disease is important before embarking on follow-up. The benefit of intensive follow-up in detecting surgically treatable recurrence is independent of stage. The survival benefit from intensive follow-up is unlikely to exceed 4% in absolute terms and harm cannot be absolutely excluded. A longer time horizon is required to ascertain whether or not intensive follow-up is an efficient use of scarce health-care resources. Translational analyses are under way, utilising tumour tissue collected from Follow-up After Colorectal Surgery trial participants, with the aim of identifying potentially prognostic biomarkers that may guide follow-up in the future.
Current Controlled Trials ISRCTN41458548.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 21, No. 32. See the NIHR Journals Library website for further project information.
The addition of cetuximab (CTX) to perioperative chemotherapy (CT) for operable colorectal liver metastases resulted in a shorter progression-free survival. Details of disease progression are ...described to further inform the primary study outcome.
A total of 257 KRAS wild-type patients were randomised to CT alone or CT with CTX. Data regarding sites and treatment of progressive disease were obtained for the 109 (CT n=48, CT and CTX n=61) patients with progressive disease at the cut-off date for analysis of November 2012.
The liver was the most frequent site of progression (CT 67% (32/48); CT and CTX 66% (40/61)). A higher proportion of patients in the CT and group had multiple sites of progressive disease (CT 8%, 4/48; CT and CTX 23%, 14/61 P=0.04). Further treatment for progressive disease is known for 84 patients of whom 69 received further CT, most frequently irinotecan based. Twenty-two patients, 11 in each arm, received CTX as a further line agent.
Both the distribution of progressive disease and further treatment are as expected for such a cohort. The pattern of disease progression seen is consistent with failure of systemic micrometastatic disease control rather than failure of local disease control following liver surgery.
Following primary surgical and adjuvant treatment for colorectal cancer, many patients are routinely followed up with blood carcinoembryonic antigen (CEA) testing.
To determine how the CEA test ...result should be interpreted to inform the decision to undertake further investigation to detect treatable recurrences.
Two studies were conducted: (1) a Cochrane review of existing studies describing the diagnostic accuracy of blood CEA testing for detecting colorectal recurrence; and (2) a secondary analysis of data from the two arms of the FACS (Follow-up After Colorectal Surgery) trial in which CEA testing was carried out.
The secondary analysis was based on data from 582 patients recruited into the FACS trial between 2003 and 2009 from 39 NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence and followed up for 5 years. CEA testing was undertaken in general practice.
In the systematic review we identified 52 studies for meta-analysis, including in aggregate 9717 participants (median study sample size 139, interquartile range 72-247). Pooled sensitivity at the most commonly recommended threshold in national guidelines of 5 µg/l was 71% 95% confidence interval (CI) 64% to 76% and specificity was 88% (95% CI 84% to 92%). In the secondary analysis of FACS data, the diagnostic accuracy of a single CEA test was less than was suggested by the review area under the receiver operating characteristic curve (AUC) 0.74, 95% CI 0.68 to 0.80. At the commonly recommended threshold of 5 µg/l, sensitivity was estimated as 50.0% (95% CI 40.1% to 59.9%) and lead time as about 3 months. About four in 10 patients without a recurrence will have at least one false alarm and six out of 10 tests will be false alarms (some patients will have multiple false alarms, particularly smokers). Making decisions to further investigate based on the trend in serial CEA measurements is better (AUC for positive trend 0.85, 95% CI 0.78 to 0.91), but to maintain approximately 70% sensitivity with 90% specificity it is necessary to increase the frequency of testing in year 1 and to apply a reducing threshold for investigation as measurements accrue.
The reference standards were imperfect and the main analysis was subject to work-up bias and had limited statistical precision and no external validation.
The results suggest that (1) CEA testing should not be used alone as a triage test; (2) in year 1, testing frequency should be increased (to monthly for 3 months and then every 2 months); (3) the threshold for investigating a single test result should be raised to 10 µg/l; (4) after the second CEA test, decisions to investigate further should be made on the basis of the trend in CEA levels; (5) the optimal threshold for investigating the CEA trend falls over time; and (6) continuing smokers should not be monitored with CEA testing. Further research is needed to explore the operational feasibility of monitoring the trend in CEA levels and to externally validate the proposed thresholds for further investigation.
This study is registered as PROSPERO CRD42015019327 and Current Controlled Trials ISRCTN93652154.
The main FACS trial and this substudy were funded by the National Institute for Health Research Health Technology Assessment programme.
The adaptive immune response to colorectal cancer is important for survival. Less is understood about the role of innate lymphocytes, such as Natural Killer (NK) cells, which are abundant in human ...liver.
Samples of fresh liver (n = 21) and tumour (n = 11) tissue were obtained from patients undergoing surgical resection of colorectal liver metastases. Flow cytometry was used to analyse the presence and phenotype of NK cells, as compared to T cells, in the tumour and liver tissue. Results were correlated with survival.
NK cells were poorly recruited to the tumours (distant liver tissue 38.3%, peritumoural liver 34.2%, tumour 12.9%, p = 0.0068). Intrahepatic and intratumoural NK cells were KIR (killer immunoglobulin-like receptor)loNKG2Ahi whereas circulating NK cells were KIRhiNKG2Alo. By contrast T cells represented 65.7% of the tumour infiltrating lymphocytes. Overall survival was 43% at 5 years, with the 5-year survival for individuals with a T cell rich infiltrate being 60% (95% CI 17-93%) and for those with a low T cell infiltrate being 0% (95% CI 0-48%). Conversely individuals with higher levels of NK cells in the tumour had an inferior outcome, although there were insufficient numbers to reach significance (median survivals: NKHi 1.63 years vs NKLo 3.92 years).
T cells, but not NK cells, are preferentially recruited to colorectal liver metastases. NK cells within colorectal metastases have an intrahepatic and potentially tolerogenic, rather than a peripheral, phenotype. Similar to primary tumours, the magnitude of the T cell infiltrate in colorectal metastases is positively associated with survival.
Purpose
Clinical trials suggest that intensive surveillance of colon cancer (CC) survivors to detect recurrence increases curative-intent treatment, although any survival benefit of surveillance as ...currently practiced appears modest. Realizing the potential of surveillance will require tools for identifying patients likely to benefit and for optimizing testing regimens. We describe and validate a model for predicting outcomes for any schedule of surveillance in CC survivors with specified age and cancer stage.
Methods
A Markov process parameterized based on individual-level clinical trial data generates natural history events for simulated patients. A utilization submodel simulates surveillance and diagnostic testing. We validate the model against outcomes from the follow-up after colorectal surgery (FACS) trial.
Results
Prevalidation sensitivity analysis showed no parameter influencing curative-intent treatment by > 5.0% or overall five-year survival (OS5) by > 1.5%. In validation, the proportion of recurring subjects predicted to receive curative-intent treatment fell within FACS 95% CI for carcinoembryonic antigen (CEA)-intensive, computed tomography (CT)-intensive, and combined CEA+CT regimens, but not for a minimum surveillance regimen, where the model overestimated recurrence and curative treatment. The observed OS5 fell within 95% prediction intervals for all regimens.
Conclusion
The model performed well in predicting curative surgery for three of four FACS arms. It performed well in predicting OS5 for all arms.
Personalized treatment approaches for patients with limited liver metastases from colorectal cancer are critically needed. By leveraging three large, independent cohorts of patients with colorectal ...liver metastases (n = 336), we found that a proliferative subtype associated with elevated CIN70 scores is linked to immune exclusion, increased metastatic proclivity, and inferior overall survival in colorectal liver metastases; however, high CIN70 scores generate a therapeutic vulnerability to DNA-damaging therapies leading to improved treatment responses. We propose CIN70 as a candidate biomarker to personalize systemic treatment options for patients with metastatic colorectal cancer. These findings are potentially broadly applicable to other human cancers.
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