Cetuximab plus irinotecan administered biweekly with reduced infusion time to heavily pretreated patients with metastatic colorectal cancer and related RAS and BRAF mutation status.

Metastatic colorectal cancer (mCRC) is treated with cetuximab 250 mg/m2 administered weekly over 1 hour or biweekly (q2w) over 3.5 hours when combined with irinotecan. This prospective study investigated cetuximab 500 mg/m2 plus irinotecan 180 mg/m2 administered q2w over 1.5 hours independent of RAS or BRAF mutation status in mCRC patients in a third-line setting. The intention-to-treat population included 181 patients. No patients had complete response, 18% had partial responses (PR) and 48% stable disease (SD). For cetuximab, a relative dose intensity of ≥90% was reached in 78% and for irinotecan in 67% of the patients. Grade 3 to 4 toxicities were pain (17%), fatigue (9%), neutropenia (8%), diarrhea (8%), rash (8%), infection (7%) and hypersensitivity (3%). No deaths occurred. Next-generation sequencing in 96.7% of the patients revealed that 50.3% had RAS and BRAFV600E wild type (WT), with a mutation type (MT) in 45.1% of the RAS and 4.4% of the BRAFV600E genes. In patients with RAS-WT and RAS-MT tumors, a PR was obtained in 32% and 4% (P = .000003) and an SD in 43% and 53%, respectively, with a superior PFS (6.2 vs 3.7 months; hazard ratio [HR] 2.12, P = .00001) and OS (12.9 vs 8.8 months; HR 1.71, P = .0008). Treatment efficacy was poor in 7.4% of patients with an RAS mutation outside KRAS exon 2 and in 38% of patients with KRAS exon 2 mutations. Administration of cetuximab and irinotecan q2w, shortening treatment time from 3.5 to 1.5 hours, is recommended as standard therapy.

TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial.

BACKGROUND: TAS-102 (trifluridine-tipiracil) has shown a significant overall survival benefit compared with placebo in patients with chemorefractory metastatic colorectal cancer. Inspired by the encouraging results of a small phase 1-2 study, C-TASK FORCE, which evaluated the combination of TAS-102 plus bevacizumab in patients with chemorefractory metastatic colorectal cancer, we aimed to compare the efficacy of TAS-102 plus bevacizumab versus TAS-102 monotherapy in patients receiving refractory therapy for metastatic colorectal cancer . METHODS: This investigator-initiated, open-label, randomised, phase 2 study enrolled patients (aged ≥18 years) with metastatic colorectal from four cancer centres in Denmark. The main inclusion criteria were histopathologically confirmed metastatic colorectal cancer refractory or intolerant to a fluoropyrimidine, irinotecan, oxaliplatin, and cetuximab or panitumumab (only for RAS wild-type), and WHO performance status of 0 or 1. Previous therapy with bevacizumab, aflibercept, ramucirumab, or regorafenib was allowed but not mandatory. Participants were enrolled and randomly assigned (1:1) in block sizes of two, four, or six by a web-based tool to receive oral TAS-102 (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) alone or combined with intravenous bevacizumab (5 mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Treatment assignment was not masked, and randomisation was stratified by institution and RAS mutation status. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2016-005241-23. FINDINGS: From Aug 24, 2017, to Oct 31, 2018, 93 patients were enrolled and randomly assigned to TAS-102 (n=47) or TAS-102 plus bevacizumab (n=46). The clinical cut-off date was Feb 15, 2019, after a median follow-up of 10·0 months (IQR 6·8-14·0). Median progression-free survival was 2·6 months (95% CI 1·6-3·5) in the TAS-102 group versus 4·6 months (3·5-6·5) in the TAS-102 plus bevacizumab group (hazard ratio 0·45 [95% CI 0·29-0·72]; p=0·0015). The most frequent grade 3 or worse adverse event was neutropenia (18 [38%] of 47 in the TAS-102 monotherapy group vs 31 [67%] of 46 in the TAS-102 plus bevacizumab group). Serious adverse events were observed in 21 (45%) patients in the TAS-102 group and 19 (41%) in the TAS-102 plus bevacizumab group. No deaths were deemed treatment related. INTERPRETATION: In patients with chemorefractory metastatic colorectal cancer, TAS-102 plus bevacizumab, as compared with TAS-102 monotherapy, was associated with a significant and clinically relevant improvement in progression-free survival with tolerable toxicity. The combination of TAS-102 plus bevacizumab could be a new treatment option for patients with refractory metastatic colorectal cancer and could be a practice-changing development. FUNDING: Servier.

Clinical value of serum hyaluronan and propeptide of type III collagen in patients with pancreatic cancer.

Hyaluronan (HA) and collagen are highly expressed in pancreatic cancer (PC) stroma. HA and collagen accumulation increase tumor interstitial fluid pressure, compromising blood flow and drug penetration. The aim of this biomarker study was to determine the clinical utility of serum HA and the propeptide of type III collagen (PRO-C3) in patients with PC. A cohort from the Danish BIOPAC study (NCT03311776) including patients with histologically confirmed pancreatic ductal adenocarcinoma (n = 809), ampullary carcinoma (n = 44), distal biliary tract cancer (n = 31), chronic pancreatitis (n = 15), intraductal papillary mucinous neoplasm (n = 41), duodenal adenoma (n = 7) and no cancer (n = 25). Healthy controls were available for serum HA (n = 141) and PRO-C3 (n = 8). The main outcome was overall survival (OS) of patients with PC in relation to pretreatment serum HA and PRO-C3 levels. Patients with PC had higher baseline serum HA and PRO-C3 than healthy subjects and patients with benign conditions. Pretreatment serum baseline HA and PRO-C3 in patients with PC were associated with poorer survival and PRO-C3 remained prognostic also after adjusting for age, performance status, stage, the presence of liver and peritoneum metastasis, and CA19-9. Detection of HA and PRO-C3 may be useful in differentiating between malignant and benign pancreatic conditions. Serum HA and PRO-C3 were prognostic for OS in patients with PC.

Prognostic impact of Charlson's Age-Comorbidity Index and other risk factors in patients with pancreatic cancer.

OBJECTIVES: Few studies have evaluated the impact of risk factors and comorbidity on overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). The aim was to investigate the prognostic importance of Charlson's age-comorbidity index (CACI) and other risk factors on prognosis in a clinical real-world cohort of PDAC patients. METHODS: A total of 1,159 patients with PDAC who had received at least one cycle of adjuvant or palliative chemotherapy were included from the Danish BIOPAC study. We analysed OS according to CACI, tobacco smoking, alcohol intake, performance status (PS), BMI and diabetes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for OS using Cox proportional hazards regression. RESULTS: At the end of follow-up, 994 (86%) patients had died. The median OS was 298 days for all patients (range 3-3010) and shortest in patients with stage IV. No association with short OS was seen for CACI > 2, diabetes, alcohol abuse, tobacco smoking, hypertension, and high BMI. Multivariate analysis showed that stage (IV vs. I: HR = 9.05, 95% CI 5.17-15.84), PS (2 vs. 0: HR = 3.67, 2.92-4.61) and treatment with angiotensin-converting enzyme inhibitors (yes vs. no: HR = 1.31, 1.06-1.61) were independent negative prognostic factors. CONCLUSIONS: We found that CACI, diabetes, tobacco smoking, alcohol abuse, hypertension, and high BMI were not associated with OS in a real-world cohort of patients with PDAC treated with chemotherapy. Only stage and PS were prognostic parameters.

Involving patients and nurses in choosing between two validated questionnaires to identify chemotherapy-induced peripheral neuropathy before implementing in clinical practice-A qualitative study.

AIMS AND OBJECTIVES: To explore from a nurse and patient perspective what questionnaire-"Functional assessment of cancer treatment gynecological group neurotoxicity" or "Oxaliplatin-Associated Neuropathy Questionnaire"-best describes chemotherapy-induced peripheral neuropathy and its influence on everyday life in a comprehensive and meaningful way, prior to implementation in daily practice. BACKGROUND: Patients experience chemotherapy-induced peripheral neuropathy during and after chemotherapy for colorectal cancer with oxaliplatin. This neuropathy is difficult to describe for patients and to identify for nurses. To address the specific needs of patients and improve identification of neuropathy and its influence on everyday life, we wanted to implement a questionnaire in clinical practice. DESIGN: A phenomenological hermeneutic frame of reference was used. METHOD: Semi-structured interviews with 15 patients and two focus groups with eight cancer nurses were used for data collection. Data were organised and interpreted by content analytical steps in a hermeneutical process. COREQ checklist was used in reporting of the study. RESULTS: The analysis resulted in two main themes (a) "To dig deeper" with sub-themes "to identify the line between acceptable and nonacceptable chemotherapy-induced peripheral neuropathy," and "searching for a precise description." (b). "When everything is interrelated" with sub-themes "to be aware of different perspectives and understandings" and "recognise potential pitfalls." CONCLUSION: Involving patients and nurses in choosing between the two questionnaires revealed that neither alone was sufficient to describe the patients' experiences. Instead, it seems essential to implement both questionnaires, using the answers as a basis for a dialogue to address the patients' specific needs. RELEVANCE FOR CLINICAL PRACTICE: Using patients and nurses perspectives in a complementary way may provide a solid foundation before starting an implementation process in clinical practice. However, attention must be paid to potential barriers and facilitators as well as the fact that a successful implementing process requires leadership and information sharing.

ABCG2 Protein Levels and Association to Response to First-Line Irinotecan-Based Therapy for Patients with Metastatic Colorectal Cancer.

In this study we investigated the use of cancer cell protein expression of ABCG2 to predict efficacy of systemic first-line irinotecan containing therapy in patients with metastatic colorectal cancer (mCRC). From a Danish national cohort, we identified 119 mCRC patients treated with irinotecan containing therapy in first-line setting. Among these, 108 were eligible for analyses. Immunohistochemistry (IHC) analyses were performed on the primary tumor tissue in order to classify samples as high or low presence of ABCG2 protein. Data were then associated with patient outcome (objective response (OR), progression free survival (PFS) and overall survival (OS)). ABCG2 protein expression in the basolateral membrane was high (score 3+) in 33% of the patients. Exploratory analyses revealed a significant interaction between ABCG2 score, adjuvant treatment and OR (p = 0.041) in the 101 patients with evaluable disease. Patients with low ABCG2 (score 0-2) and no prior adjuvant therapy had a significantly higher odds ratio of 5.6 (Confidence Interval (CI) 1.68-18.7; p = 0.005) for obtaining OR. In contrast, no significant associations between ABCG2 expression and PFS or OS were found. These results suggest that measurement of the ABCG2 drug efflux pump might be used to select patients with mCRC for irinotecan treatment. However, additional studies are warranted before conclusions regarding a clinical use can be made. Moreover, patients with high ABCG2 immunoreactivity could be candidates for specific ABCG2 inhibition treatment in combination with irinotecan.

The effect of postoperative gemcitabine on overall survival in patients with resected pancreatic cancer: A nationwide population-based Danish register study.

Background: Adjuvant chemotherapy following curative resection is the standard treatment for pancreatic adenocarcinoma (PC). Randomized clinical trials using gemcitabine have shown a median overall survival (mOS) of 2 years and a 5-year survival rate of 15-20%. However, the effect of gemcitabine outside these trials is less clear. We examined the effect of postoperative gemcitabine on survival in an unselected cohort of patients receiving curative resection for PC in Denmark during a five-year period. Material and methods: From 1 May 2011 to 30 April 2016, 731 patients treated with curative resection were identified in the Danish Pancreatic Cancer Database (DPCD). Thirty patients died within 10 weeks postoperatively; 78 received other regimens or preoperative chemotherapy and were excluded. Of the remaining 623 patients, the chemotherapy (CT) group (n = 409, 66%) received gemcitabine within 10 weeks after resection, whereas the non-chemotherapy (NCT) group (n = 214, 34%) did not receive CT within 10 weeks. Results: CT patients were slightly younger than NCT patients but did not otherwise differ in baseline characteristics. The CT group showed a mOS of 24 months (95% CI; 21-27) and a 5-year survival rate of 22% (95% CI; 17-27); the NCT group had a mOS of 22 months (95% CI; 16-26, p = .27) and a 5-year survival rate of 26% (95% CI; 19-34, p = .66). Most patients (415/623) had lymph node metastases. Of these patients, those in the CT group (n = 280) had significantly longer mOS [20 months (95% CI; 18-24)] than those in the NCT group (n = 135) [14 months (95% CI; 11-17)]. Conclusions: In this national Danish cohort of PC patients undergoing resection between 2011 and 2016, the survival after postoperative gemcitabine was similar to that reported in previous clinical trials. However, the survival advantage of postoperative gemcitabine was limited to patients with lymph node metastases.

Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report.

BACKGROUND: We previously reported that in pathogenic mismatch repair (path_MMR) variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated. METHODS: The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only path_MMR variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis. RESULTS: Ninety-nine path_MMR carriers had no cancer prior to or at first colonoscopy, but subsequently developed colon cancer. Among these, 96 were 65 years of age or younger at diagnosis, and included 77 path_MLH1, 17 path_MSH2, and 2 path_MSH6 carriers. The number of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years after previous colonoscopy were 9, 43, 31 and 13, respectively. Of these, 2, 8, 4 and 3 were stage III, respectively, and only one stage IV (interval 2.5-3.5 years) disease. Ten-year crude survival after colon cancer were 93, 94 and 82% for stage I, II and III disease, respectively (p < 0.001). Ten-year crude survival when the last colonoscopy had been < 1.5, 1.5-2.5, 2.5-3.5 or > 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively (p = 0.91). CONCLUSIONS: In path_MLH1 and path_MSH2 carriers, more advanced colon cancer stage was associated with poorer survival, whereas time since previous colonoscopy was not. Although the numbers are limited, together with our previously reported findings, these results may be in conflict with the view that follow-up of path_MMR variant carriers with colonoscopy intervals of less than 3 years provides significant benefit.

Is the accuracy of preoperative MRI stage in rectal adenocarcinoma influenced by tumour height?

AIM: To our knowledge, no prior studies have addressed the possible effects of tumour height on the accuracy of preoperative magnetic resonance imaging (MRI)-based staging relative to postoperative histopathological assessments in patients with adenocarcinoma of the rectum (RC). This study aimed to investigate whether the accuracy of preoperative MRI stage in RC is influenced by tumour height. METHODS: A total of 489 consecutive RC patients scheduled for curative treatment between 2009 and 2013 were included. Of the 489 patients, 133 patients had preoperative chemoradiotherapy (CRT), and 356 patients underwent primary surgery. Low, mid and high RC were defined as a tumour <5 cm, 5-10 cm and >10 cm from the anal verge, respectively. Diagnostic MRI and, for patients with CRT, re-staging MRI features including tumour T-stage (mrT), distance between the tumour border and the distance to the mesorectal fascia (mrMRF), extramural tumour depth (mrEMD), extramural vascular invasion (mrEMVI) and nodal involvement (mrN) were correlated with the corresponding postoperative histopathological findings. RESULTS: There were 115, 186 and 188 patients with low RC, mid RC and high RC, respectively. For all patients, the correlations between mrT and pT and between mrMRF and pCRM were not influenced by tumour height. None of the correlations between mrEMD, mrEMVI and mrN and the corresponding postoperative histopathological findings significantly differed for tumours of different heights. For patients with CRT, a remarkable proportion with low RC were overstaged as ymrT3 compared to ypT0-2. CONCLUSIONS: The ability to preoperatively use MRI to accurately stage is not influenced by tumour height. For patients with preoperative CRT, low RC may be MRI overstaged due to post-radiation fibrosis. We found that mrEMD predicts pEMD reliably and should therefore be considered in treatment decisions. Although new MRI techniques are emerging, preoperative RC staging remains incompletely definitive in daily clinical practice.

Associations between primary tumor RAS, BRAF and PIK3CA mutation status and metastatic site in patients with chemo-resistant metastatic colorectal cancer.

BACKGROUND: Several studies have investigated correlations between metastatic pattern and mutation status in patients with colorectal cancer (CRC). However, most of the studies were small and heterogeneously designed and further research is needed to confirm previous results. In this study, we investigated the association between RAS (KRAS or NRAS), BRAF, PIK3CA mutations and metastatic pattern in patients with metastatic (m) CRC. MATERIAL AND METHODS: This study reviewed Danish biobank and database of patients with mCRC who received cetuximab and irinotecan, independent of RAS mutation status, after fluoropyrimidine, oxaliplatin and irinotecan treatment failure. The database contained information regarding tumor mutation status of KRAS, NRAS, BRAF and PIK3CA genes. RESULTS: Totally, 448 patients were included. On multivariate analyses, RAS mutations were significantly associated with increased odds of having lung metastases at diagnosis of mCRC (odds ratio (OR) = 2.04; 95% confidence interval (CI) = 1.32-3.17), and PIK3CA mutations with decreased odds of peritoneal metastases at diagnosis of mCRC (OR = 0.10; 95%CI = 0.01-0.79). On multivariate analyses of the hazard of developing metastases at any time during follow-up, RAS mutations were significantly associated with increased hazard of lung (hazard ratio (HR) = 1.34; 95%CI = 1.04-1.72) and ovarian metastases (HR = 3.12; 95%CI = 1.05-9.24), BRAF V600E mutation was associated with increased hazard of skin metastases (HR = 6.82; 95%CI = 1.86-25.02) and PIK3CA mutations with decreased hazard of peritoneal metastases (HR = 0.31; 95%CI = 0.11-0.86). CONCLUSIONS: This study indicated that in patients with mCRC, RAS mutations are associated with increased risk of lung and ovary metastases. BRAF V600E is associated with increased risk of skin metastases, and PIK3CA mutation with decreased risk of peritoneal metastases.

Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer.

BACKGROUND: No biomarker exists to guide the optimal choice of chemotherapy for patients with metastatic colorectal cancer. We examined the copy numbers (CN) of topoisomerase I (TOP1) as well as the ratios of TOP1/CEN-20 and TOP1/CEN-2 as biomarkers for irinotecan efficacy in patients with metastatic colorectal cancer. METHODS: From a national cohort, we identified 163 patients treated every third week with irinotecan 350 mg/m2 as second-line therapy. Among these 108 were eligible for analyses and thus entered the study. Primary tumors samples were collected and tissue microarray (TMA) blocks were produced. FISH analysis was performed using two probe-mixes: TOP1/CEN-20 and TOP1/CEN-2. Only samples harboring all three signals (TOP1, CEN-20 and CEN-2) using FISH were included in the analyses. RESULTS: In the TOP1/CEN-20 probe-mix the median TOP1- and CEN-20 CN were 4.46 (range: 1.5-9.5) and 2.00 (range: 0.55-4.55), respectively. The median TOP1- and CEN-2 CN in the TOP1/CEN-2 probe-mix, were 4.57 (range: 1.82-10.43) and 1.98 (range: 1.22-6.14), respectively. The median TOP1/CEN-20 ratio and TOP1/CEN-2 ratio were 1.25 (range: 0.92-2.90) and 2.05 (range: 1.00-6.00), respectively. None of the markers TOP1 CN, TOP1/CEN-20-ratio or TOP1/CEN-2-ratio were associated with progression free survival, overall survival or baseline characteristics. Yet, we observed a borderline association for a stepwise increase of the TOP1 CN in relation to objective response as hazard ratio were 1.35 (95% CI 0.96-1.90; p = 0.081). CONCLUSIONS: We verified a borderline significant association between increasing TOP1 CN and objective response as previously reported. Applying the probes representing CEN-20 and CEN-2, in order to investigate the ratios of TOP1/CEN-20 and TOP1/CEN-2 provided no further information in search of a biomarker driven patient stratification. Other biomarkers to be paired with TOP1 CN are therefore highly warranted.

Risk factors for brain metastases in patients with metastatic colorectal cancer.

BACKGROUND: Brain metastases (BM) from colorectal cancer (CRC) are rare, but the incidence is suspected to rise as treatment of metastatic (m) CRC improves. The aim of this study was to identify possible biological and clinical characteristics at initial presentation of mCRC that could predict later risk of developing BM. Furthermore, we wished to estimate the incidence of BM in long-term surviving patients. MATERIAL AND METHODS: We conducted a retrospective study on a Danish multicenter cohort of patients with mCRC who received cetuximab and irinotecan (CetIri) as third-line treatment. All patients had previously progression on 5-FU, irinotecan and oxaliplatin containing regimens and received CetIri treatment independent of RAS mutations status. We subsequently performed KRAS, NRAS, BRAF, PIK3CA, PTEN, ERBB2 and EGFR sequencing of DNA extracted from primary tumor tissue. RESULTS: Totally, 480 patients were included in our study. BM were diagnosed in 42 [8.8%; 95% confidence interval (CI) 6.4-11.6%] patients. Patients with BM had a significantly longer survival from mCRC diagnosis than non-BM patients (median = 32 versus 28 months, p = 0.001). On univariate cox regression analysis, the risk of developing BM was significantly increased in patients with rectal cancer (HR = 3.9; 95% CI = 1.2-13.3), metachronous metastatic disease (HR = 2.3; 95% CI = 1.2-4.4) and lung metastases (HR = 4.2; 95% CI = 2.2-7.9). On multivariate cox regression analysis only lung metastases were significantly associated BM (HR = 3.5; 95% CI = 1.8-6.8). None of the investigated mutations were associated with BM. CONCLUSION: The incidence of BM was 8.8% in patients with mCRC who received third-line therapy. The most important risk factor for developing BM was lung metastases. Furthermore, rectal cancer, metachronous metastatic disease and long survival were linked to BM development.

The potential diagnostic value of serum microRNA signature in patients with pancreatic cancer.

Biomarkers for early diagnosis of patients with pancreatic cancer (PC) are needed. Our aim was to identify panels of miRNAs in serum in combination with CA 19-9 for use in the diagnosis of PC. Four hundred seventeen patients with PC were included prospectively from Denmark (n = 306) and Germany (n = 111). Controls included 59 patients with chronic pancreatitis (CP) and 248 healthy subjects (HS). MiRNAs were analyzed in pretreatment serum samples from 3 cohorts: discovery cohort (754 human miRNAs, TaqMan(®) Human MicroRNA assay, Applied Biosystem; PC n = 133, controls n = 72); training cohort (34 miRNAs, real-time qPCR using the Fluidigm BioMark™ System; PC n = 198, controls n = 184); validation cohort (13 miRNAs, real-time qPCR using the Fluidigm BioMark™ System; PC n = 86, controls n = 51). We found that 34 miRNAs in serum from PC patients in the discovery cohort were expressed differently than in controls. These miRNAs were tested in the training cohort, and four diagnostic panels were constructed that included 5 or 12 miRNAs (miR-16, -18a, -20a, -24, -25, -27a, -29c, -30a.5p, -191, -323.3p, -345 and -483.5p). Diagnostic accuracy of detecting PC in the training cohort was AUC (Index I 0.85; II 0.87; III 0.85; IV 0.95; CA 19-9 0.93); specificity (I 0.71; II 0.76; III 0.66; IV 0.90 (fixed sensitivity at 0.85); CA 19-9 0.93). Combining serum CA 19-9 and Index II best discriminated Stages I and II PC from HS [AUC 0.93 (0.90-0.96), sensitivity 0.77 (0.69-0.84), specificity 0.94 (0.90-0.96) and accuracy 0.88 (0.84-0.91)]. In conclusion, we identified four diagnostic panels based on 5 or 12 miRNAs in serum that could distinguish patients with PC from HS and CP.

A nationwide retrospective study of perioperative chemotherapy for gastroesophageal adenocarcinoma: tolerability, outcome, and prognostic factors.

BACKGROUND: Recent clinical trials have demonstrated the benefit and feasibility of perioperative chemotherapy for treatment of gastroesophageal adenocarcinoma (GEA). Despite convincing results, patients entering such trials usually represent only a fraction of those who are candidates for treatment. Confirmation of trial-reported effects and tolerability in unselected cohorts is therefore required. The aims of this study were to confirm the safety and efficacy of perioperative chemotherapy for resectable GEA and to delineate risks of treatment failure. METHODS: We conducted a national retrospective cohort analysis of patients admitted for perioperative chemotherapy for resectable GEA. Regimens were epirubicin and capecitabine combined with oxaliplatin or cisplatin. RESULTS: The intention-to-treat analysis included 271 patients. Eighty-seven percent of patients completed preoperative chemotherapy, and 63 % received radical resection. Age >70 years (odds ratio 2.58) and hypoalbuminemia (odds ratio 4.10) were independent predictors of not undergoing scheduled surgery (P = 0.033). Grade 3 or higher febrile neutropenia, fatigue, and diarrhea were common in the oxaliplatin group (n = 128), but hypomagnesaemia and tinnitus/hearing loss were more common in the cisplatin group (n = 135). The median overall survival was 26.4 months, and the 1- and 2-year survival rates were 76 and 53 %, respectively. Performance status >0 (hazard ratio 1.64) and elevated serum lactate dehydrogenase (hazard ratio 3.03) were independent predictors of poor prognosis (P ≤ 0.05). CONCLUSIONS: Perioperative chemotherapy is feasible and well tolerated in patients with good performance status and low incidence of comorbidities.

Review on adjuvant chemotherapy for rectal cancer - why do treatment guidelines differ so much?

BACKGROUND: The use of postoperative adjuvant chemotherapy is controversial for rectal adenocarcinoma. Both international and national guidelines display a great span varying from recommending no adjuvant chemotherapy at all, over single drug 5-fluororuacil (5-FU), to combinations of 5-FU/oxaliplatin. METHODS: A review of the literature was made identifying 24 randomized controlled trials on adjuvant treatment of rectal cancer based on about 10 000 patients. The trials were subdivided into a number of clinically relevant subgroups. RESULTS: As regards patients treated with preoperative (chemo) radiotherapy, four randomized studies were found where use of adjuvant chemotherapy showed no benefit in survival. Three trials were found in which a subset of patients received preoperative (chemo) radiotherapy. Two of these trials showed a statistically significant benefit of adjuvant chemotherapy. Twenty trials were identified in which the patients did not receive preoperative (chemo) radiotherapy, including five Asian studies in which a statistically significant benefit from adjuvant chemotherapy was reported. CONCLUSIONS: Most of the data found did not support the use of postoperative adjuvant chemotherapy for patients already treated with preoperative (chemo) radiotherapy. For patients not treated preoperatively, several studies support the use of single agent 5-FU chemotherapy. Treatment guidelines seem to differ according to if preoperative chemoradiation is considered of importance for use of adjuvant chemotherapy and if adjuvant colon cancer studies are considered transferrable to rectal cancer patients regardless of the molecular differences.

FCGR2A and FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin +/- cetuximab.

BACKGROUND: Polymorphisms of genes encoding the Fcy receptors (Fc fragment of IgG receptor 2A (FCGR2A) and 3A (FCGR3A)), which influence their affinity for the Fc fragment, have been linked to the pharmacodynamics of monoclonal antibodies. Most studies have been limited by small samples sizes and have reported inconsistent associations between the FCGR2A and the FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab. We investigated the association of these polymorphisms and clinical outcome in a large cohort of mCRC patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin (Nordic FLOX) +/- cetuximab in the NORDIC-VII study (NCT00145314). METHODS: 504 and 497 mCRC patients were evaluable for the FCGR2A and FCGR3A genotyping, respectively. Genotyping was performed on TaqMan ABI HT 7900 (Applied Biosystems, Foster City, CA, USA) with pre-designed SNP genotyping assays for FCGR2A (rs1801274) and FCGR3A (rs396991). RESULTS: The response rate for patients with the FCGR2A R/R genotype was significantly increased when cetuximab was added to Nordic FLOX (31% versus 53%, interaction P = 0.03), but was not significantly different compared to the response rate of patients with the FCGR2A H/H or H/R genotypes given the same treatment. A larger increase in response rate with the addition of cetuximab to Nordic FLOX in patients with KRAS mutated tumors and the FCGR2A R/R genotype was observed (19% versus 50%, interaction P = 0.04). None of the FCGR3A polymorphisms were associated with altered response when cetuximab was added to Nordic FLOX (interaction P = 0.63). Neither of the FCGR polymorphisms showed any significant associations with progression-free survival or overall survival. CONCLUSION: Patients with KRAS mutated tumors and the FCGR2A R/R polymorphism responded poorly when treated with chemotherapy only, and experienced the most benefit of the addition of cetuximab in terms of response rate.

The CAIRO4 study: the role of surgery of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastases of colorectal cancer--a randomized phase III study of the Dutch Colorectal Cancer Group (DCCG).

BACKGROUND: There is no consensus regarding resection of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastatic colorectal cancer (CRC). A potential benefit of resection of the primary tumour is to prevent complications of the primary tumour in later stages of the disease. We here propose a randomized trial in order to demonstrate that resection of the primary tumour improves overall survival. METHODS/DESIGN: The CAIRO4 study is a multicentre, randomized, phase III study of the Dutch Colorectal Cancer Group (DCCG). Patients with synchronous unresectable metastases of CRC and few or absent symptoms of the primary tumour are randomized 1:1 between systemic therapy only, and resection of the primary tumour followed by systemic therapy. Systemic therapy will consist of fluoropyrimidine-based chemotherapy in combination with bevacizumab. The primary objective of this study is to determine the clinical benefit in terms of overall survival of initial resection of the primary tumour. Secondary endpoints include progression free survival, surgical morbidity, quality of life and the number of patients requiring resection of the primary tumour in the control arm. DISCUSSION: The CAIRO4 study is a multicentre, randomized, phase III study that will assess the benefit of resection of the primary tumour in patients with synchronous metastatic CRC. TRIAL REGISTRATION: The CAIRO4 study is registered at clinicaltrials.gov (NCT01606098).

MicroRNA biomarkers in whole blood for detection of pancreatic cancer.

IMPORTANCE: Biomarkers for the early diagnosis of patients with pancreatic cancer are needed to improve prognosis. OBJECTIVES: To describe differences in microRNA expression in whole blood between patients with pancreatic cancer, chronic pancreatitis, and healthy participants and to identify panels of microRNAs for use in diagnosis of pancreatic cancer compared with the cancer antigen 19-9 (CA19-9). DESIGN, SETTING, AND PARTICIPANTS: A case-control study that included 409 patients with pancreatic cancer and 25 with chronic pancreatitis who had been included prospectively in the Danish BIOPAC (Biomarkers in Patients with Pancreatic Cancer) study (July 2008-October 2012) plus 312 blood donors as healthy participants. The microRNA expressions in pretreatment whole blood RNA samples were collected and analyzed in 3 randomly determined subcohorts: discovery cohort (143 patients with pancreatic cancer, 18 patients with chronic pancreatitis, and 69 healthy participants), training cohort (180 patients with pancreatic cancer, 1 patient with chronic pancreatitis, and 199 healthy participants), and validation cohort (86 patients with pancreatic cancer, 7 patients with chronic pancreatitis, and 44 healthy participants); 754 microRNAs were screened in the discovery cohort and 38 microRNAs in the training cohort and 13 microRNAs in the validation cohort. MAIN OUTCOMES AND MEASURES: Identification of microRNA panels (classifiers) for diagnosing pancreatic cancer. RESULTS: The discovery cohort demonstrated that 38 microRNAs in whole blood were significantly dysregulated in patients with pancreatic cancer compared with controls. These microRNAs were tested in the training cohort and 2 diagnostic panels were constructed comprising 4 microRNAs in index I (miR-145, miR-150, miR-223, miR-636) and 10 in index II (miR-26b, miR-34a, miR-122, miR-126*, miR-145, miR-150, miR-223, miR-505, miR-636, miR-885.5p). The test characteristics for the training cohort were index I area under the curve (AUC) of 0.86 (95% CI, 0.82-0.90), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.64 (95% CI, 0.57-0.71); index II AUC of 0.93 (95% CI, 0.90-0.96), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.85 (95% CI, 0.80-0.85); and CA19-9 AUC of 0.90 (95% CI, 0.87-0.94), sensitivity of 0.86 (95% CI, 0.80-0.90), and specificity of 0.99 (95% CI, 0.96-1.00). Performances were strengthened in the validation cohort by combining panels and CA19-9 (index I AUC of 0.94 [95% CI, 0.90-0.98] and index II AUC of 0.93 [95% CI, 0.89-0.97]). Compared with CA19-9 alone, the AUC for the combination of index I and CA19-9 was significantly higher (P = .01). The performance of the panels in patients with stage IA-IIB pancreatic cancer was index I AUC of 0.80 (95% CI, 0.73-0.87); index I and CA19-9 AUC of 0.83 (95% CI, 0.76-0.90); index II AUC of 0.91 (95% CI, 0.87-0.94); and index II and CA19-9 AUC of 0.91 (95% CI, 0.86-0.95). CONCLUSIONS AND RELEVANCE: This study identified 2 diagnostic panels based on microRNA expression in whole blood with the potential to distinguish patients with pancreatic cancer from healthy controls. Further research is necessary to understand whether these have clinical implications for early detection of pancreatic cancer and how much this information adds to serum CA19-9.

TRIFLURIDINE/TIPIRACIL (FTD/TPI) with or without bevacizumab in previously treated patients with esophago-gastric adenocarcinoma, a randomised phase III trial.

Background: Trifluridine-tipiracil has shown a survival benefit compared with placebo in patients with chemorefractory metastatic esophago-gastric adenocarcinoma. We aimed to compare the efficacy of trifluridine-tipiracil plus bevacizumab vs trifluridine-tipiracil monotherapy in pre-treated patients with metastatic esophago-gastric adenocarcinoma. Methods: This investigator-initiated, open-label, randomized trial enrolled patients with metastatic esophago-gastric adenocarcinoma. The main inclusion criteria were patients with pre-treated metastatic esophago-gastric adenocarcinoma, and WHO performance status 0 or 1. Participants were randomly assigned (1:1) to receive oral trifluridine-tipiracil (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) alone or combined with bevacizumab (5 mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Randomisation was stratified by sex and treatment line. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2018-004845-18. Findings: From Oct 1, 2019, to Sept 30, 2021, 103 patients were enrolled and randomly assigned to trifluridine-tipiracil (n = 53) or trifluridine-tipiracil plus bevacizumab (n = 50). The clinical cut-off date was March 1st, 2023, after a median follow-up of 36.6 months. Median progression-free survival was 3.1 months (95% CI 2.0-4.3) in the trifluridine-tipiracil group vs 3.9 months (3.0-6.3) in the trifluridine-tipiracil plus bevacizumab group (hazard ratio 0.68, 95% CI 0.46-1.02; p = 0.058). The most frequent grade 3 or worse adverse event was neutropenia, observed in 26 (49%) patients in the trifluridine-tipiracil group vs 23 patients (46%) in the trifluridine-tipiracil plus bevacizumab group. At least one hospitalization was observed in 21 patients (40%) in the trifluridine-tipiracil group and 22 patients (44%) in the trifluridine-tipiracil plus bevacizumab group. No deaths were deemed treatment related. Interpretation: In patients with pre-treated metastatic esophago-gastric cancer, trifluridine-tipiracil plus bevacizumab, compared to trifluridine-tipiracil monotherapy, did not significantly prolong progression-free survival. The combination of trifluridine-tipiracil with bevacizumab was well tolerated without increase in severe neutropenia and no new safety signals. Funding: Servier, Roche.

Oxaliplatin causes increased offset analgesia during chemotherapy - a feasibility study.

OBJECTIVES: Offset analgesia (OA) is the phenomenon where the perceived pain intensity to heat stimulation disproportionally decreases after a slight decrease in stimulation temperature. The neural mechanisms of OA are not fully understood, but it appears that both peripheral and central temporal filtering properties are involved. Chemotherapy with oxaliplatin often causes acute peripheral sensory neuropathy, and manifests primarily as a cold induced allodynia. The aim of this exploratory patient study was to investigate if OA was affected by the neurotoxic effects of adjuvant oxaliplatin treatment. METHODS: OA was assessed in 17 colon cancer patients during 12 cycles of adjuvant oxaliplatin treatment. The OA response was estimated as the decrease in pain intensity caused by a temperature decrease from 46 °C to 45 °C. Changes in the OA during the treatment period was estimated using a mixed linear model and corrected for multiple comparisons by Sidak's test. RESULTS: OA was increased significantly when assessed before the 2nd, 3rd, 5th, 6th, 9th, and 10th treatment cycle compared to the first (baseline) treatment (p<0.05). CONCLUSIONS: OA is generally decreased in persons suffering from chronic pain or peripheral neuropathy as compared to healthy controls. But in the present study, OA increased during chemotherapy with oxaliplatin. The underlying mechanism of this unexpected increase should be further explored.