IMPORTANCE Intensive follow-up after surgery for colorectal cancer is common practice but is based on limited evidence. OBJECTIVE To assess the effect of scheduled blood measurement of ...carcinoembryonic antigen (CEA) and computed tomography (CT) as follow-up to detect recurrent colorectal cancer treatable with curative intent. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial in 39 National Health Service hospitals in the United Kingdom; 1202 eligible participants were recruited between January 2003 and August 2009 who had undergone curative surgery for primary colorectal cancer, including adjuvant treatment if indicated, with no evidence of residual disease on investigation. INTERVENTIONS Participants were randomly assigned to 1 of 4 groups: CEA only (n = 300), CT only (n = 299), CEA+CT (n = 302), or minimum follow-up (n = 301). Blood CEA was measured every 3 months for 2 years, then every 6 months for 3 years; CT scans of the chest, abdomen, and pelvis were performed every 6 months for 2 years, then annually for 3 years; and the minimum follow-up group received follow-up if symptoms occurred. MAIN OUTCOMES AND MEASURES The primary outcome was surgical treatment of recurrence with curative intent; secondary outcomes were mortality (total and colorectal cancer), time to detection of recurrence, and survival after treatment of recurrence with curative intent. RESULTS After a mean 4.4 (SD, 0.8) years of observation, cancer recurrence was detected in 199 participants (16.6%; 95% CI, 14.5%-18.7%) overall; 71 of 1202 participants (5.9%; 95% CI, 4.6%-7.2%) were treated for recurrence with curative intent, with little difference according to Dukes staging (stage A, 5.1% 13/254; stage B, 6.1% 34/553; stage C, 6.2% 22/354). Surgical treatment of recurrence with curative intent was 2.3% (7/301) in the minimum follow-up group, 6.7% (20/300) in the CEA group, 8% (24/299) in the CT group, and 6.6% (20/302) in the CEA+CT group. Compared with minimum follow-up, the absolute difference in the percentage of patients treated with curative intent in the CEA group was 4.4% (95% CI, 1.0%-7.9%; adjusted odds ratio OR, 3.00; 95% CI, 1.23-7.33), in the CT group was 5.7% (95% CI, 2.2%-9.5%; adjusted OR, 3.63; 95% CI, 1.51-8.69), and in the CEA+CT group was 4.3% (95% CI, 1.0%-7.9%; adjusted OR, 3.10; 95% CI, 1.10-8.71). The number of deaths was not significantly different in the combined intensive monitoring groups (CEA, CT, and CEA+CT; 18.2% 164/901) vs the minimum follow-up group (15.9% 48/301; difference, 2.3%; 95% CI, −2.6% to 7.1%). CONCLUSIONS AND RELEVANCE Among patients who had undergone curative surgery for primary colorectal cancer, intensive imaging or CEA screening each provided an increased rate of surgical treatment of recurrence with curative intent compared with minimal follow-up; there was no advantage in combining CEA and CT. If there is a survival advantage to any strategy, it is likely to be small. TRIAL REGISTRATION isrctn.org Identifier: 41458548
Summary Background Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free ...survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. Methods This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18–80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m2 , folinic acid 200 mg/m2 (DL form) or 100 mg/m2 (L form) on days 1–2 plus bolus, and fluorouracil 400 mg/m2 (bolus) and 600 mg/m2 (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. This trial is registered with ClinicalTrials.gov , number NCT00006479. Findings Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6–9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68–1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0–83·4) in the perioperative chemotherapy group and 54·3 months (41·9–79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6–58·3) in the perioperative chemotherapy group versus 47·8% (40·3–55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. Interpretation We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients. Funding Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.
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Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with ...5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer.
This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1–14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13.
Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37–60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6–59·1) in the capecitabine group compared with 36·4 months (29·7–44·5) in the observation group (adjusted hazard ratio HR 0·81, 95% CI 0·63–1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55–0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30–44) in the observation group (adjusted HR 0·75, 95% CI 0·58–0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6–35·9) in the capecitabine group and 17·5 months (12·0–23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8–46·3) in the capecitabine group and 17·4 months (12·0–23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related.
Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting.
Cancer Research UK and Roche.
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Exosomes are secreted vesicles which can transmit molecular cargo between cells. Exosomal microRNAs (exomiRs) have drawn much attention in recent years because there is increasing evidence to suggest ...that loading of microRNAs into exosomes is not a random process. Preclinical studies have identified functional roles for exomiRs in influencing many hallmarks of cancer. Mechanisms underpinning their actions, such as exomiR receptors (“miRceptors”), are now becoming apparent. Even more exciting is the fact that exomiRs are highly suitable candidates for use as non-invasive biomarkers in an era of personalized cancer medicine.
•MicroRNAs packaged and secreted in exosomes are termed “exomiRs”.•Sorting of miRNAs into exosomes is a selective process.•Cancer and stroma-derived exomiRs influence many hallmarks of cancer.•ExomiRs are highly promising cancer biomarkers.
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To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with resected biliary tract cancer.
ASCO convened an Expert Panel to conduct a systematic ...review of the literature on adjuvant therapy for resected biliary tract cancer and provide recommended care options for this patient population.
Three phase III randomized controlled trials, one phase II trial, and 16 retrospective studies met the inclusion criteria.
Based on evidence from a phase III randomized controlled trial, patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy for a duration of 6 months. The dosing used in this trial is described in the qualifying statements, while it should be noted that the dose of capecitabine may also be determined by institutional and regional practices. Patients with extrahepatic cholangiocarcinoma or gallbladder cancer and a microscopically positive surgical resection margin (R1 resection) may be offered chemoradiation therapy. A shared decision-making approach is recommended, considering the risk of harm and potential for benefit associated with radiation therapy for patients with extrahepatic cholangiocarcinoma or gallbladder cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .
Summary Background Surgical resection alone is regarded as the standard of care for patients with liver metastases from colorectal cancer, but relapse is common. We assessed the combination of ...perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Methods This parallel-group study reports the trial's final data for progression-free survival for a protocol unspecified interim time-point, while overall survival is still being monitored. 364 patients with histologically proven colorectal cancer and up to four liver metastases were randomly assigned to either six cycles of FOLFOX4 before and six cycles after surgery or to surgery alone (182 in perioperative chemotherapy group vs 182 in surgery group). Patients were centrally randomised by minimisation, adjusting for centre and risk score. The primary objective was to detect a hazard ratio (HR) of 0·71 or less for progression-free survival. Primary analysis was by intention to treat. Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152). This trial is registered with ClinicalTrials.gov , number NCT00006479. Findings In the perioperative chemotherapy group, 151 (83%) patients were resected after a median of six (range 1–6) preoperative cycles and 115 (63%) patients received a median six (1–8) postoperative cycles. 152 (84%) patients were resected in the surgery group. The absolute increase in rate of progression-free survival at 3 years was 7·3% (from 28·1% 95·66% CI 21·3–35·5 to 35·4% 28·1–42·7; HR 0·79 0·62–1·02; p=0·058) in randomised patients; 8·1% (from 28·1% 21·2–36·6 to 36·2% 28·7–43·8; HR 0·77 0·60–1·00; p=0·041) in eligible patients; and 9·2% (from 33·2% 25·3–41·2 to 42·4% 34·0–50·5; HR 0·73 0·55–0·97; p=0·025) in patients undergoing resection. 139 patients died (64 in perioperative chemotherapy group vs 75 in surgery group). Reversible postoperative complications occurred more often after chemotherapy than after surgery (40/159 25% vs 27/170 16%; p=0·04). After surgery we recorded two deaths in the surgery alone group and one in the perioperative chemotherapy group. Interpretation Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients. Funding Swedish Cancer Society, Cancer Research UK, Ligue Nationale Contre le Cancer, US National Cancer Institute, Sanofi-Aventis.
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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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Testing for carcino‐embryonic antigen (CEA) in the blood is a recommended part of follow‐up to detect recurrence of colorectal cancer following primary curative treatment. There is ...substantial clinical variation in the cut‐off level applied to trigger further investigation.
Objectives
To determine the diagnostic performance of different blood CEA levels in identifying people with colorectal cancer recurrence in order to inform clinical practice.
Search methods
We conducted all searches to January 29 2014. We applied no language limits to the searches, and translated non‐English manuscripts. We searched for relevant reviews in the MEDLINE, EMBASE, MEDION and DARE databases. We searched for primary studies (including conference s) in the Cochrane Central Register of Controlled Trials (CENTRAL), in MEDLINE, EMBASE, and the Science Citation Index & Conference Proceedings Citation Index – Science. We identified ongoing studies by searching WHO ICTRP and the ASCO meeting library.
Selection criteria
We included cross‐sectional diagnostic test accuracy studies, cohort studies, and randomised controlled trials (RCTs) of post‐resection colorectal cancer follow‐up that compared CEA to a reference standard. We included studies only if we could extract 2 x 2 accuracy data. We excluded case‐control studies, as the ratio of cases to controls is determined by the study design, making the data unsuitable for assessing test accuracy.
Data collection and analysis
Two review authors (BDN, IP) assessed the quality of all articles independently, discussing any disagreements. Where we could not reach consensus, a third author (BS) acted as moderator. We assessed methodological quality against QUADAS‐2 criteria. We extracted binary diagnostic accuracy data from all included studies as 2 x 2 tables. We conducted a bivariate meta‐analysis. We used the xtmelogit command in Stata to produce the pooled estimates of sensitivity and specificity and we also produced hierarchical summary ROC plots.
Main results
In the 52 included studies, sensitivity ranged from 41% to 97% and specificity from 52% to 100%. In the seven studies reporting the impact of applying a threshold of 2.5 µg/L, pooled sensitivity was 82% (95% confidence interval (CI) 78% to 86%) and pooled specificity 80% (95% CI 59% to 92%). In the 23 studies reporting the impact of applying a threshold of 5 µg/L, pooled sensitivity was 71% (95% CI 64% to 76%) and pooled specificity 88% (95% CI 84% to 92%). In the seven studies reporting the impact of applying a threshold of 10 µg/L, pooled sensitivity was 68% (95% CI 53% to 79%) and pooled specificity 97% (95% CI 90% to 99%).
Authors' conclusions
CEA is insufficiently sensitive to be used alone, even with a low threshold. It is therefore essential to augment CEA monitoring with another diagnostic modality in order to avoid missed cases. Trying to improve sensitivity by adopting a low threshold is a poor strategy because of the high numbers of false alarms generated. We therefore recommend monitoring for colorectal cancer recurrence with more than one diagnostic modality but applying the highest CEA cut‐off assessed (10 µg/L).
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