Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase 3 CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group.

BACKGROUND: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor. PATIENTS AND METHODS: This randomized phase 3 trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1:1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098. RESULTS: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n= 103 without upfront PTR, n=101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (IQR 59-71). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% CI 16.0-22.2) compared to 20.1 months (95% CI 17.0-25.1) in the upfront PTR arm (p = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (p=0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm. CONCLUSION: of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptoms of the primary tumor does not result in a survival benefit. This practice should no longer be considered standard of care.

Perioperative Systemic Therapy Versus Cytoreductive Surgery and HIPEC Alone for Resectable Colorectal Peritoneal Metastases: Patient-Reported Outcomes of a Randomized Phase II Trial.

BACKGROUND: As part of a randomized phase II trial in patients with isolated resectable colorectal peritoneal metastases (CPMs), the present study compared patient-reported outcomes (PROs) of patients treated with perioperative systemic therapy versus cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone. Also, PROs of patients receiving perioperative systemic therapy were explored. PATIENTS AND METHODS: Eligible patients were randomized to perioperative systemic therapy (experimental) or CRS-HIPEC alone (control). PROs were assessed using EORTC QLQ-C30, QLQ-CR29, and EQ-5D-5L questionnaires at baseline, after neoadjuvant treatment (experimental), and at 3 and 6 months postoperatively. Linear mixed modeling was used to compare five predefined PROs (visual analog scale, global health status, physical functioning, fatigue, C30 summary score) between arms and to longitudinally analyze PROs in the experimental arm. RESULTS: Of 79 analyzed patients, 37 (47%) received perioperative systemic therapy. All predefined PROs were comparable between arms at all timepoints and returned to baseline at 3 or 6 months postoperatively. The experimental arm had worsening of fatigue [mean difference (MD) + 14, p = 0.001], loss of appetite (MD + 15, p = 0.003), hair loss (MD + 18, p < 0.001), and loss of taste (MD + 27, p < 0.001) after neoadjuvant treatment. Except for loss of appetite, these PROs returned to baseline at 3 or 6 months postoperatively. CONCLUSIONS: In patients with resectable CPM randomized to perioperative systemic therapy or CRS-HIPEC alone, PROs were comparable between arms and returned to baseline postoperatively. Together with the trial's previously reported feasibility and safety data, these findings show acceptable tolerability of perioperative systemic therapy in this setting.

First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study.

BACKGROUND: Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results. METHODS: TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1-5 and 8-12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1-14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS. RESULTS: At 1 September 2020, median OS was 22.3 months (95% CI: 18.0-23.7) with TT-B and 17.7 months (95% CI: 12.6-19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55-1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings. CONCLUSIONS: TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy. CLINICAL TRIAL INFORMATION: NCT02743221 (clinicaltrials.gov).

Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study.

BACKGROUND: We designed an open-label, noncomparative phase II study to assess the safety and efficacy of first-line treatment with trifluridine/tipiracil plus bevacizumab (TT-B) and capecitabine plus bevacizumab (C-B) in untreated patients with unresectable metastatic colorectal cancer (mCRC) who were not candidates for combination with cytotoxic chemotherapies. PATIENTS AND METHODS: From 29 April 2016 to 29 March 2017, 153 patients were randomly assigned (1:1) to either TT-B (N = 77) or C-B (N = 76). The primary end point was progression-free survival (PFS). The primary PFS analysis was performed after 100 events (radiological progression or death) were observed. Secondary end points included overall survival (OS), quality of life (QoL; QLQ-C30 and QLQ-CR29 questionnaires), and safety. RESULTS: Median (range) duration of treatment was 7.8 (6.0-9.7) months and 6.2 (4.1-9.1) months in the TT-B and C-B groups, respectively. Median (range) PFS was 9.2 (7.6-11.6) and 7.8 (5.5-10.1) months, respectively. Median (range) OS was 18 (15.2 to NA) and 16.2 (12.5 to NA) months, respectively. QoL questionnaires showed no relevant changes over time for either treatment. Therapies were well tolerated. Patients receiving TT-B had more grade ≥3 neutropenia (47% versus 5% with C-B). Patients receiving C-B had more grade ≥3 hand-foot syndrome (12% versus 0% with TT-B) and grade ≥3 diarrhea (8% versus 1% with TT-B), consistent with the known safety profiles of these agents. CONCLUSION: TT-B treatment showed promising clinical activity in untreated patients with unresectable mCRC ineligible for intensive therapy, with an acceptable safety profile and no clinically relevant changes in QoL. CLINICAL TRIAL INFORMATION: NCT02743221 (ClinicalTrials.gov).

Interconnectivity between molecular subtypes and tumor stage in colorectal cancer.

BACKGROUND: There are profound individual differences in clinical outcomes between colorectal cancers (CRCs) presenting with identical stage of disease. Molecular stratification, in conjunction with the traditional TNM staging, is a promising way to predict patient outcomes. We investigated the interconnectivity between tumor stage and tumor biology reflected by the Consensus Molecular Subtypes (CMSs) in CRC, and explored the possible value of these insights in patients with stage II colon cancer. METHODS: We performed a retrospective analysis using clinical records and gene expression profiling in a meta-cohort of 1040 CRC patients. The interconnectivity of tumor biology and disease stage was assessed by investigating the association between CMSs and TNM classification. In order to validate the clinical applicability of our findings we employed a meta-cohort of 197 stage II colon cancers. RESULTS: CMS4 was significantly more prevalent in advanced stages of disease (stage I 9.8% versus stage IV 38.5%, p < 0.001). The observed differential gene expression between cancer stages is at least partly explained by the biological differences as reflected by CMS subtypes. Gene signatures for stage III-IV and CMS4 were highly correlated (r = 0.77, p < 0.001). CMS4 cancers showed an increased progression rate to more advanced stages (CMS4 compared to CMS2: 1.25, 95% CI: 1.08-1.46). Patients with a CMS4 cancer had worse survival in the high-risk stage II tumors compared to the total stage II cohort (5-year DFS 41.7% versus 100.0%, p = 0.008). CONCLUSIONS: Considerable interconnectivity between tumor biology and tumor stage in CRC exists. This implies that the TNM stage, in addition to the stage of progression, might also reflect distinct biological disease entities. These insights can potentially be utilized to optimize identification of high-risk stage II colon cancers.

The association between preoperative fatigue and instrumental activities in daily living with complications and length of hospital stay in patients undergoing colorectal surgery.

BACKGROUND: The incidence of colorectal cancer (CRC) is highest among the elderly. An important treatment modality is surgery. After surgery, due to poor functional recovery, some elderly have an increased risk for complications and prolonged length of hospital stay (LOS). Preoperative elevated levels of fatigue and impaired functioning in instrumental activities of daily living (iADL) might be associated with these outcomes, and may, therefore, be helpful to recognize patients with elevated risk for complications or prolonged LOS, who should undergo more thorough functional assessment. AIMS: This exploratory study aims to assess whether physical fatigue, reduced activity and/or iADL, assessed preoperatively, are associated with postoperative complications and prolonged LOS, in elderly patients undergoing surgery for CRC. METHODS: We performed an exploratory prospective study in older (≥ 65 years) patients (n = 57) who were scheduled to undergo elective surgery for colorectal cancer. Fatigue and iADL functioning were assessed with questionnaires. Multivariable regression analyses were used to examine the relationship of fatigue and iADL with complications and LOS. RESULTS: IADL was not associated with complications or LOS. Fatigue was not associated with complications. Patients with higher fatigue had increased LOS in the univariable analyses but not in the multivariable analyses after adjustment for nutritional status and neoadjuvant treatment. DISCUSSION: We found that fatigue was associated with increased LOS in the univariable analysis. The results from the multivariable analysis and path analysis indicate, however, that this is likely not a causal relationship; the observed relationship between physical fatigue and LOS appears to be confounded by nutritional status and by having received neoadjuvant treatment. CONCLUSIONS: Although fatigue is a predictor for increased LOS, assessment of fatigue and iADL has no additional value for identifying elderly at risk for poor functional outcome after CRC surgery.

Adjuvant hepatic arterial infusion pump chemotherapy and resection versus resection alone in patients with low-risk resectable colorectal liver metastases - the multicenter randomized controlled PUMP trial.

BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 µg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone. DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival. TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands.

BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.

Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study.

BACKGROUND: The phase 3 CAIRO3 study showed that capecitabine plus bevacizumab (CAP-B) maintenance treatment after six cycles capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in metastatic colorectal cancer (mCRC) patients is effective, without compromising quality of life. In this post hoc analysis with updated follow-up and data regarding sidedness, we defined subgroups according to RAS/BRAF mutation status and mismatch repair (MMR) status, and investigated their influence on treatment efficacy. PATIENTS AND METHODS: A total of 558 patients with previously untreated mCRC and stable disease or better after six cycles CAPOX-B induction treatment were randomised to either CAP-B maintenance treatment (n = 279) or observation (n = 279). Upon first progression, patients were to receive CAPOX-B reintroduction until second progression (PFS2, primary end point). We centrally assessed RAS/BRAF mutation status and MMR status, or used local results if central assessment was not possible. Intention-to-treat stratified Cox models adjusted for baseline covariables were used to examine whether treatment efficacy was modified by RAS/BRAF mutation status. RESULTS: RAS, BRAF mutations, and MMR deficiency were detected in 240/420 (58%), 36/381 (9%), and 4/279 (1%) patients, respectively. At a median follow-up of 87 months (IQR 69-97), all mutational subgroups showed significant improvement from maintenance treatment for the primary end point PFS2 [RAS/BRAF wild-type: hazard ratio (HR) 0.57 (95% CI 0.39-0.84); RAS-mutant: HR 0.74 (0.55-0.98); V600EBRAF-mutant: HR 0.28 (0.12-0.64)] and secondary end points, except for the RAS-mutant subgroup regarding overall survival. Adjustment for sidedness instead of primary tumour location yielded comparable results. Although right-sided tumours were associated with inferior prognosis, both patients with right- and left-sided tumours showed significant benefit from maintenance treatment. CONCLUSIONS: CAP-B maintenance treatment after six cycles CAPOX-B is effective in first-line treatment of mCRC across all mutational subgroups. The benefit of maintenance treatment was most pronounced in patients with RAS/BRAF wild-type and V600EBRAF-mutant tumours. CLINICALTRIALS.GOV NUMBER: NCT00442637.

How health-related quality of life assessment should be used in advanced colorectal cancer clinical trials.

Traditionally, the efficacy of cancer treatment in patients with advance or metastatic disease in clinical studies has been studied using overall survival and more recently tumor-based end points such as progression-free survival, measurements of response to treatment. However, these seem not to be the relevant clinical end points in current situation if such end points were no validated as surrogate of overall survival to demonstrate the clinical efficacy. Appropriate, meaningful, primary patient-oriented and patient-reported end points that adequately measure the effects of new therapeutic interventions are then crucial for the advancement of clinical research in metastatic colorectal cancer to complement the results of tumor-based end points. Health-related quality of life (HRQoL) is effectively an evaluation of quality of life and its relationship with health over time. HRQoL includes the patient report at least of the way a disease or its treatment affects its physical, emotional and social well-being. Over the past few years, several phase III trials in a variety of solid cancers have assessed the incremental value of HRQoL in addition to the traditional end points of tumor response and survival results. HRQoL could provide not only complementary clinical data to the primary outcomes, but also more precise predictive and prognostic value. This end point is useful for both clinicians and patients in order to achieve the dogma of precision medicine. The present article examines the use of HRQoL in phase III metastatic colorectal cancer clinical trials, outlines the importance of HRQoL assessment methods, analysis, and results presentation. Moreover, it discusses the relevance of including HRQoL as a primary/co-primary end point to support the progression-free survival results and to assess efficacy of treatment in the advanced disease setting.

Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group.

BACKGROUND: Hand-foot syndrome (HFS) is a common side-effect of capecitabine. S-1 is an oral fluoropyrimidine with comparable efficacy to capecitabine in gastrointestinal cancers but associated with a lower incidence of HFS in Asian patients. This study compares the incidence of HFS between S-1 and capecitabine as first-line treatment in Western metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: Patients with previously untreated mCRC and planned treatment with fluoropyrimidine monochemotherapy were randomized 1 : 1 to receive either capecitabine (1250 mg/m2 orally for patients <70 years; 1000 mg/m2 for patients ≥70 years, twice daily on days 1-14) or S-1 (30 mg/m2 orally twice daily on days 1-14) in 3-weekly cycles, with bevacizumab optional in both groups. The primary endpoint was the incidence of any grade HFS, as assessed by both physicians and patients (diaries). Secondary endpoints included grade 3 HFS, other toxicities, relative dose intensity, progression-free survival, response rate and overall survival. RESULTS: A total of 161 patients were randomized in 27 centres. The incidence of any grade HFS as assessed by physicians was 73% in the capecitabine group (n = 80) and 45% in the S-1 group (n = 80) [odds ratio (95% confidence interval) 0.31 (0.16-0.60), P = 0.0005]. The incidence of grade 3 HFS was 21% and 4% (P = 0.003), respectively. Patient-assessed any grade HFS was 84% and 58%, respectively (P = 0.004). Grade 3 anorexia was more common in the S-1 group (3% versus 13%, P = 0.03). Median relative dose intensity was 88% in the capecitabine group and 95% in the S-1 group (P = 0.026). There were no statistically significant differences in median progression-free survival, response rate and overall survival rates. CONCLUSION: Treatment with S-1 in Western mCRC patients is associated with a significantly lower incidence of HFS compared with capecitabine, with comparable efficacy. CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT01918852.

Ethnic differences in colon cancer care in the Netherlands: a nationwide registry-based study.

BACKGROUND: Ethnic differences in colon cancer (CC) care were shown in the United States, but results are not directly applicable to European countries due to fundamental healthcare system differences. This is the first study addressing ethnic differences in treatment and survival for CC in the Netherlands. METHODS: Data of 101,882 patients diagnosed with CC in 1996-2011 were selected from the Netherlands Cancer Registry and linked to databases from Statistics Netherlands. Ethnic differences in lymph node (LN) evaluation, anastomotic leakage and adjuvant chemotherapy were analysed using stepwise logistic regression models. Stepwise Cox regression was used to examine the influence of ethnic differences in adjuvant chemotherapy on 5-year all-cause and colorectal cancer-specific survival. RESULTS: Adequate LN evaluation was significantly more likely for patients from 'other Western' countries than for the Dutch (OR 1.09; 95% CI 1.01-1.16). 'Other Western' patients had a significantly higher risk of anastomotic leakage after resection (OR 1.24; 95% CI 1.05-1.47). Patients of Moroccan origin were significantly less likely to receive adjuvant chemotherapy (OR 0.27; 95% CI 0.13-0.59). Ethnic differences were not fully explained by differences in socioeconomic and hospital-related characteristics. The higher 5-year all-cause mortality of Moroccan patients (HR 1.64; 95% CI 1.03-2.61) was statistically explained by differences in adjuvant chemotherapy receipt. CONCLUSION: These results suggest the presence of ethnic inequalities in CC care in the Netherlands. We recommend further analysis of the role of comorbidity, communication in patient-provider interaction and patients' health literacy when looking at ethnic differences in treatment for CC.

Comparison of symptom clusters associated with fatigue in older and younger survivors of colorectal cancer.

PURPOSE: Cancer-related fatigue (CRF) is one of the most frequently reported symptoms in cancer survivors. To be able to optimally treat CRF, knowledge of symptoms that interact with CRF is helpful. During aging, changes occur in body composition with progressive deterioration in physiological functions and metabolic processes causing a decline of adaptive capacity. Therefore, symptoms caused by cancer and its treatment might coexist in different symptom clusters in older cancer survivors, compared to younger survivors. The purpose of this analysis was to identify and compare symptom clusters that include CRF between older and younger survivors of colorectal cancer (CRC). METHODS: Data were drawn from a cross-sectional study from the Netherlands Cancer Registry. In total, 1698 stage I and II CRC survivors diagnosed from 2000 to 2009 completed questionnaires on fatigue and psychological distress. Survivors were categorized in two groups based on age (≤65 versus >65 years) Symptom clusters were assessed using principal component analysis. A sensitivity analysis was performed on the results with categorical principal component analysis. RESULTS: In both age groups, three components including two symptom clusters were identified: an emotional symptom cluster containing anxiety, fatigue, and depression; a pain symptom cluster containing pain and insomnia; and a third component containing dyspnea only. CONCLUSIONS: Symptom clusters in survivors of CRC appear to be independent of age. In treating CRC survivors for fatigue, regardless of age, it is advisable to assess depression and anxiety and, if necessary, refer for further diagnosis and treatment.

Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers.

Microsatellite instability (MSI) has been associated with favourable survival in early stage colorectal cancer (CRC) compared to microsatellite stable (MSS) CRC. The BRAF V600E mutation has been associated with worse survival in MSS CRC. This mutation occurs in 40% of MSI CRC and it is unclear whether it confers worse survival in this setting. The prognostic value of KRAS mutations in both MSS and MSI CRC remains unclear. We examined the effect of BRAF and KRAS mutations on survival in stage II and III MSI colon cancer patients. BRAF exon 15 and KRAS exon 2-3 mutation status was assessed in 143 stage II (n = 85) and III (n = 58) MSI colon cancers by high resolution melting analysis and sequencing. The relation between mutation status and cancer-specific (CSS) and overall survival (OS) was analyzed using Kaplan-Meier and Cox regression analysis. BRAF V600E mutations were observed in 51% (n = 73) and KRAS mutations in 16% of cases (n = 23). Patients with double wild-type cancers (dWT; i.e., BRAF and KRAS wild-type) had a highly favourable survival with 5-year CSS of 93% (95% CI 84-100%), while patients with cancers harbouring mutations in either BRAF or KRAS, had 5-year CSS of 76% (95% CI 67-85%). In the subgroup of stage II patients with dWT cancers no cancer-specific deaths were observed. On multivariate analysis, mutation in either BRAF or KRAS vs. dWT remained significantly prognostic. Mutations in BRAF as well as KRAS should be analyzed when considering these genes as prognostic markers in MSI colon cancers.

A multi-centred randomised trial of radical surgery versus adjuvant chemoradiotherapy after local excision for early rectal cancer.

BACKGROUND: Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5-20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients. METHODS/STUDY DESIGN: In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients. DISCUSSION: The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery. TRIAL REGISTRATION: NCT02371304 , registration date: February 2015.

Prospective Dutch colorectal cancer cohort: an infrastructure for long-term observational, prognostic, predictive and (randomized) intervention research.

BACKGROUND: Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients' outcomes. With only 5-15% of patients participating in clinical trials, generalizability of results is poor. Moreover, current trials often lack the capacity for post-hoc subgroup analyses. For this purpose, a large observational cohort study, serving as a multiple trial and biobanking facility, was set up by the Dutch Colorectal Cancer Group (DCCG). METHODS/DESIGN: The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nationwide observational cohort study in the Netherlands (yearly CRC incidence of 15 500). All CRC patients (stage I-IV) are eligible for inclusion, and longitudinal clinical data are registered. Patients give separate consent for the collection of blood and tumor tissue, filling out questionnaires, and broad randomization for studies according to the innovative cohort multiple randomized controlled trial design (cmRCT), serving as an alternative study design for the classic RCT. Objectives of the study include: 1) systematically collected long-term clinical data, patient-reported outcomes and biomaterials from daily CRC practice; and 2) to facilitate future basic, translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods, even for studies with stringent inclusion criteria. RESULTS: Seven months after initiation 650 patients have been enrolled, eight centers participate, 15 centers await IRB approval and nine embedded cohort- or cmRCT-designed studies are currently recruiting patients. CONCLUSION: This cohort provides a unique multidisciplinary data, biobank, and patient-reported outcomes collection initiative, serving as an infrastructure for various kinds of research aiming to improve treatment outcomes in CRC patients. This comprehensive design may serve as an example for other tumor types.

Vascular endothelial growth factor D expression is a potential biomarker of bevacizumab benefit in colorectal cancer.

BACKGROUND: Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects. METHODS: We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population. RESULTS: Patients with low expression of VEGF-D (0, 1þ) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CBþCBM), 0.21; 95% CI, 0.08­0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13­0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2þ PFS HR, 0.67; 95% CI, 0.45­1.00; OS HR, 0.82; 95% CI, 0.52­1.30; VEGF-D 3þ PFS HR, 0.77; 95% CI, 0.50­1.17; OS HR, 1.28; 95% CI, 0.79­2.09) (P interaction o0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression. CONCLUSIONS: The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation.

Clinical validation study of genetic markers for capecitabine efficacy in metastatic colorectal cancer patients.

BACKGROUND AND AIM: Pharmacogenetic studies continue to search for pretreatment predictors of chemotherapeutic efficacy and toxicity in metastatic colorectal cancer. Both genome-wide association studies and candidate gene studies have yielded potential genetic markers for chemosensitivity. We conducted a clinical association study, validating the effect of specific genetic markers cited in recently published papers on the efficacy of the oral 5-fluoro-uracil prodrug capecitabine. PATIENTS AND METHODS: Germline DNA was collected for 268 metastatic colorectal cancer patients from the CAIRO trial, a multicenter phase III trial, randomizing between combined or sequential first-line treatment with capecitabine, irinotecan, and oxaliplatin. Genotyping was performed for eight single-nucleotide polymorphisms (SNPs), using high-resolution melting curves. Four SNPs are located in the MTRR gene, and another four SNPs showed significant association with 5-fluoro-uracil cytotoxicity in a recent in-vitro genome-wide association study. The primary endpoint was progression-free survival (PFS); secondary endpoints were objective response and overall survival. RESULTS: In patients receiving capecitabine monotherapy, rs4702484, located in ADCY2 and close to MTRR, was associated with slightly reduced PFS for homozygous wild-type patients (CC 6.2 vs. CT 8.0 months; P=0.018). For the other selected genetic markers, we found no association with PFS, overall survival, or radiologic response upon treatment with capecitabine, either in the total study population or in the capecitabine monotherapy subgroup. CONCLUSION: With the exception of rs4702484, we found no evidence of an effect on capecitabine chemosensitivity for any of the studied SNPs. More specifically, variants in methionine synthase reductase (MTRR) are not likely associated with capecitabine efficacy.

Preoperative chemoradiotherapy for esophageal or junctional cancer.

BACKGROUND: The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery with surgery alone in this patient population. METHODS: We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. RESULTS: From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy-surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy-surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P=0.003). CONCLUSIONS: Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF Kankerbestrijding]; Netherlands Trial Register number, NTR487.).